Preparation of silylamines by the dehydrogeative coupling of N—H and Si—H bonds

ABSTRACT

The present invention describes chemical systems and methods for silylating N—H bonds of aliphatic amines, said system or method comprising or consisting essentially of a mixture of (a) at least one organosilane and (b) at least one hydroxide, especially KOH, said system being preferably, but not necessarily substantially free of a transition-metal compound, and said methods comprising contacting a quantity of the organic substrate with a mixture of (a) at least one organosilane and (b) at least one strong base, under conditions sufficient to replace an N—H bond with a silyl N—Si bond.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/818,417, filed Aug. 5, 2015, which claims priority to U.S. patentapplication Ser. No. 62/033,975, filed Aug. 6, 2014; 62/094,381, filedDec. 19, 2014; and 62/141,905, filed Apr. 2, 2015, the contents of whichare incorporated by reference herein for all purposes.

GOVERNMENT RIGHTS

This invention was made with government support under Grant No.CHE1212767 awarded by the National Science Foundation. The governmenthas certain rights in the invention.

TECHNICAL FIELD

The present invention is directed at methods for silylating aromaticsubstrates, including heteroaromatic substrates, using hydroxide(especially potassium hydroxide) and silane reagents.

BACKGROUND

The ability to silylate organic moieties has attracted significantattention in recent years, owing to the utility of the silylatedmaterials in their own rights or as intermediates for other importantmaterials used, for example, in agrichemical, pharmaceutical, andelectronic material applications. Further, the ability to functionalizepolynuclear aromatic compounds with oganosilanes provides opportunitiesto take advantage of the interesting properties of these materials.

Historically, the silylation of aromatic compounds has been achieved viafree radical processes involving thermally, photochemically, or byotherwise derived radical sources. Aromatic compounds are known reactwith silicon hydrides in the gas phase at 500-850° C., in the liquidphase under autogeneous pressure at 350-500° C., in the presence ofperoxides at 135° C. under gas phase condensations, and using electricaldischarge reactions. Such reactions conditions are not amenable tonon-volatile or thermally sensitive materials.

At present, the most common approach to heteroaromatic C—Si bondconstruction involves the interception of heteroaryl lithium ormagnesium reagents with silicon electrophiles. However, this method isoften limited in scope and requires prefunctionalization of heteroarenesby using pyrophoric organometallic species in stoichiometric quantities.Powerful heteroaromatic functionalization strategies, such asMinisci-type radical substitutions and Friedel—Crafts reactions, havebeen of limited use for C—Si bond construction owing to the difficultyof generating the corresponding silyl radicals and silylium ions.

More recently, the transition metal mediated aromatic C—H silylation hasbeen described, with different systems described based on, for example,Co, Rh, Ir, Fe, Ru, Os, Ni, Pd, and Pt catalysts. But certain electronicapplications, the presence of even low levels of such residual canadversely affect the performance of the silylated materials. Similarly,in certain pharmaceutical or electronic applications, limits on residualtransition metals are fairly strict, and the ability to avoid thementirely offers benefits during post-synthesis work-up.

The present invention takes advantage of the discoveries cited herein toavoid at least some of the problems associated with previously knownmethods.

SUMMARY

The present disclosure provides new information with respect to thebutoxide catalyzed silylation of aromatic substrates as well as therecent discovery that KOH (potassium hydroxide), can be made operable asa catalyst in the present reactions. Contrary to earlier findings, ithas now been found that KOH can be an effective catalyst for the directsilylation of heteroaromatic substances with hydrosilanes under certainconditions. It now appears that by modifying the reaction conditions,this KOH catalyst system can be used with every substrate in whichpotassium tert-butoxide (or other “strong bases”) was previously shownto be effective, but where KOH was previously shown to be unworkable,for example, as described in U.S. patent application Ser. No. 14/043,929and International Application No. PCT/US2013/062963, both filed Oct. 2,2013. The use of KOH offers important practical benefits such as lowercost and toxicity, easier handling, and facilitated reaction set up andpurification. Additionally, it provides a selectivity not seen inreactions using stronger bases, including alkoxides.

This specification also discloses additional embodiments, described interms of potassium tert-butoxide, not previously explicitly described,showing a more complete set of examples of the versatility of thesemethods.

Various embodiments of the present invention provide chemical systemsfor silylating organic compounds, each system comprising or consistingessentially of a mixture of (a) at least one organosilane and (b) atleast one strong base, the definition of said strong base now alsoincluding KOH, said system also operable to silylate an aromaticprecursor when conducted preferably substantially free of atransition-metal compound. The system further comprises at least oneorganic aromatic substrate.

Other embodiments provide methods, each method comprising contacting theorganic aromatic substrate with a mixture comprising or consistingessentially of (a) at least one organosilane and (b) at least one strongbase, the definition of said strong base now also including KOH, underconditions sufficient to silylate the substrate. In some embodiments,said mixture and substrate are preferably, but not necessarily,substantially free of a transition-metal compound.

BRIEF DESCRIPTION OF THE DRAWINGS

The present application is further understood when read in conjunctionwith the appended drawings. For the purpose of illustrating the subjectmatter, there are shown in the drawings exemplary embodiments of thesubject matter; however, the presently disclosed subject matter is notlimited to the specific methods, devices, and systems disclosed. Inaddition, the drawings are not necessarily drawn to scale. In thedrawings:

FIGS. 1A and 1B illustrate examples of some of the reactions availableby the methods described herein.

FIG. 2 illustrates the scope of base-catalysed silylation of indoles. Inthese examples, KO-t-Bu is used as an exemplary base. [Si]—H=Et₃SiH,Et₂SiH₂, EtMe₂SiH, PhMe₂SiH or n-Bu₃SiH. MOM, methoxylmethyl; SEM,2-[(trimethylsilyl)ethoxy]methyl.

FIG. 3 illustrates the scope of base-catalysed silylation of N-, O- andS-containing heteroarenes. In these examples, KO-t-Bu is used as anexemplary base. See Example 6.9.1 to 6.9.51 for details. [Si]—H=Et₃SiH,Et₂SiH₂, EtMe₂SiH, PhMe₂SiH or n-Bu₃SiH.

FIGS. 4A-4E show certain synthetic applications of the base-catalysedC—H silylation. In these examples, KO-t-Bu is used as an exemplary base.FIG. 4A shows a schematic of the preparation of 142 g of C₂-silylatedindole building block 2a. FIG. 4B illustrates certain applications ofheteroarylsilanes in cross-coupling and a formal C—H borylation at C₇ ofbenzothiophene. FIG. 4C illustrates certain embodied syntheses ofselective precursors to advanced materials and polymers. FIG. 4Dillustrates the selective examples of the inventive methods used toprepare late-stage chemo- and regioselective modification of activepharmaceutical ingredients. FIG. 4E shows examples of functionalizationof arenes by oxygen-directed sp², and innate benzylic sp³ C—Hsilylation. See Examples 6.7.1 to 6.7.4 for details. [Si]=Et₃Si; i-Pr,isopropyl; dba, dibenzylideneacetone; Bpin,4,4,5,5-tetramethyl-1,3,2-dioxaborolane; TMEDA,tetramethylethylenediamine; EDOT, 3,4-ethylenedioxythiophene.

FIGS. 5A/B show conversion vs. time data for the silylation of1-methylindole with 3 equivalents of Et₃SiH and different KOH loadingsat 45° C. (time in minutes and conversions in percent). FIG. 5A showsthe overall conversion as a function of time and FIG. 5B shows the ratioof C2:C3 as a function of time. Top curves (squares) is for 20 mol % KOHand bottom curves are for 5 mol %.

FIG. 6 shows KOH catalyst loading data for the silylation of1-methylindole with 3 equivalents of Et₃SiH at 65° C.

FIG. 7 shows the results of testing representative substrates silylatedwith a KOH catalytic system. Conditions A: Starting material (0.5 mmol,1 eq); KOH (0.1 mmol, 5.6 mg, 20 mol %); SiEt₃H (1.5 mmol, 3 equiv., 240μL) in THF (0.5 mL) at 65° C. Conditions B: Starting material (0.5 mmol,1 eq); KOH (0.1 mmol, 5.6 mg, 20 mol %); SiEt₃H (0.6 mmol, 1.2 equiv.,96 μL) in THF (0.5 mL) at 45° C.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention is founded on a set of reactions, each of whichrelies on simple mixtures of organosilanes and strong bases, thedefinition of said strong bases now also including hydroxide, especiallyKOH, which together form in situ systems (the structure and nature ofthe active species is still unknown) able to silylate aromaticmolecules, especially heteroaryl compounds, in the liquid phase, withoutthe presence of transition metal catalysts, UV radiation or electrical(including plasma) discharges. These reactions are relevant as animportant advance in developing practical methods for the preparation ofproducts important for pharmaceutically and electronics applications.Importantly this reaction is of great interest since it produces onlyenvironmentally benign silicates and dihydrogen as the byproduct and canavoid toxic metal waste streams as would be observed with nearly allother approaches proposed in the literature towards this end. Theremarkable facility and regiospecificity exhibited by at least some ofthese systems provides a useful tool in the kit of chemists in thesefields.

The present disclosure includes some information previously presented inU.S. patent application Ser. No. 14/043,929 and InternationalApplication No. PCT/US2013/062963, both filed Oct. 2, 2013, as well asnew additional embodiments described in terms of potassiumtert-butoxide, not previously explicitly described, showing a morecomplete set of embodiments of the versatility of these methods. Thedisclosure further provides data related to the recent discovery thatKOH (potassium hydroxide), and other hydroxides, can be made operable asa catalyst in the present reactions. Contrary to earlier findings, ithas now been found that KOH can be an effective catalyst for the directsilylation of heteroaromatic substances with hydrosilanes under certainconditions. Whereas many of the examples provided herein are describedin terms of tert-butoxide, hydrides, etc., these examples can also beextended to include those where KOH is the operative catalyst, andembodiments described in terms of the former also extend to those usingthe latter. Likewise, comments on the operability of tert-butoxidesystems (e.g., tolerance to functional groups) are explicitly intendedto reflect also on the operability of KOH systems.

The silylation reactions described herein proceed under mild conditions,in the absence of hydrogen acceptors, ligands or additives, and isscalable to greater than 100 grams under optionally solvent-freeconditions. Substrate classes that are difficult to activate withprecious metal catalysts are silylated in good yield and with excellentregioselectivity. The derived heteroaryl silane products readily engagein versatile transformations enabling new synthetic strategies forheteroaromatic elaboration, and are useful in theirownright inpharmaceutical and materials science applications.

The present invention may be understood more readily by reference to thefollowing description taken in connection with the accompanying Figuresand Examples, all of which form a part of this disclosure. It is to beunderstood that this invention is not limited to the specific products,methods, conditions or parameters described or shown herein, and thatthe terminology used herein is for the purpose of describing particularembodiments by way of example only and is not intended to be limiting ofany claimed invention. Similarly, unless specifically otherwise stated,any description as to a possible mechanism or mode of action or reasonfor improvement is meant to be illustrative only, and the inventionherein is not to be constrained by the correctness or incorrectness ofany such suggested mechanism or mode of action or reason forimprovement. Throughout this text, it is recognized that thedescriptions refer to compositions and methods of making and using saidcompositions. That is, where the disclosure describes or claims afeature or embodiment associated with a composition or a method ofmaking or using a composition, it is appreciated that such a descriptionor claim is intended to extend these features or embodiment toembodiments in each of these contexts (i.e., compositions, methods ofmaking, and methods of using).

In the present disclosure the singular forms “a,” “an,” and “the”include the plural reference, and reference to a particular numericalvalue includes at least that particular value, unless the contextclearly indicates otherwise. Thus, for example, a reference to “amaterial” is a reference to at least one of such materials andequivalents thereof known to those skilled in the art, and so forth.

When a value is expressed as an approximation by use of the descriptor“about,” it will be understood that the particular value forms anotherembodiment. In general, use of the term “about” indicates approximationsthat can vary depending on the desired properties sought to be obtainedby the disclosed subject matter and is to be interpreted in the specificcontext in which it is used, based on its function. The person skilledin the art will be able to interpret this as a matter of routine. Insome cases, the number of significant figures used for a particularvalue may be one non-limiting method of determining the extent of theword “about.” In other cases, the gradations used in a series of valuesmay be used to determine the intended range available to the term“about” for each value. Where present, all ranges are inclusive andcombinable. That is, references to values stated in ranges include everyvalue within that range.

It is to be appreciated that certain features of the invention whichare, for clarity, described herein in the context of separateembodiments, may also be provided in combination in a single embodiment.That is, unless obviously incompatible or specifically excluded, eachindividual embodiment is deemed to be combinable with any otherembodiment(s) and such a combination is considered to be anotherembodiment. Conversely, various features of the invention that are, forbrevity, described in the context of a single embodiment, may also beprovided separately or in any sub-combination. Finally, while anembodiment may be described as part of a series of steps or part of amore general structure, each said step may also be considered anindependent embodiment in itself, combinable with others.

The transitional terms “comprising,” “consisting essentially of,” and“consisting” are intended to connote their generally in acceptedmeanings in the patent vernacular; that is, (i) “comprising,” which issynonymous with “including,” “containing,” or “characterized by,” isinclusive or open-ended and does not exclude additional, unrecitedelements or method steps; (ii) “consisting of” excludes any element,step, or ingredient not specified in the claim; and (iii) “consistingessentially of” limits the scope of a claim to the specified materialsor steps “and those that do not materially affect the basic and novelcharacteristic(s)” of the claimed invention. Embodiments described interms of the phrase “comprising” (or its equivalents), also provide, asembodiments, those which are independently described in terms of“consisting of” and “consisting essentially of” For those embodimentsprovided in terms of “consisting essentially of,” the basic and novelcharacteristic(s) is the facile operability of the methods (or thesystems used in such methods or the compositions derived therefrom) tosilylate aromatic organic moieties. In those embodiments that provide asystem or method comprises the use of a mixture consisting essentiallyof the substrate, organosilane (alternatively referred to ashydrosilane), and strong base (the definition of strong base now alsoincluding hydroxide, especially KOH), it refers to the fact that thissystem operates to silylate the substrate at rates corresponding tothose described herein under comparable conditions as described hereinwithout additional (e.g., transition metal) catalysts or plasma or UVradiation sources. While some level of transition metals may be present,they are not needed for the operability of the methods, and may beconsidered spectators for purposes of this reaction. Indeed, extensiveexperiments and analyses conducted rule out catalysis by adventitioustransition metal residues (see Examples 3.1 to 3.3). Similarly, whileother previous silylation reactions have employed plasma or UVirradiation to operate, the present invention does not require theseenergy sources. The additional presence of these energy sources shouldnot be seen as replacing the basis underlying operability of the presentmethods.

When a list is presented, unless stated otherwise, it is to beunderstood that each individual element of that list, and everycombination of that list, is a separate embodiment. For example, a listof embodiments presented as “A, B, or C” is to be interpreted asincluding the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,”or “A, B, or C.” Similarly, a designation such as C₁₋₃ includes C₁, C₂,C₃, C₁₋₂, C₂₋₃, C_(1,3), as separate embodiments, as well as C₁₋₃.

Throughout this specification, words are to be afforded their normalmeaning, as would be understood by those skilled in the relevant art.However, so as to avoid misunderstanding, the meanings of certain termswill be specifically defined or clarified.

The term “alkyl” as used herein refers to a linear, branched, or cyclicsaturated hydrocarbon group typically although not necessarilycontaining 1 to about 24 carbon atoms, preferably 1 to about 12 carbonatoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, octyl, decyl, and the like, as well as cycloalkyl groupssuch as cyclopentyl, cyclohexyl and the like. Generally, although againnot necessarily, alkyl groups herein contain 1 to about 12 carbon atoms.The term “lower alkyl” intends an alkyl group of 1 to 6 carbon atoms,and the specific term “cycloalkyl” intends a cyclic alkyl group,typically having 4 to 8, preferably 5 to 7, carbon atoms. The term“substituted alkyl” refers to alkyl groups substituted with one or moresubstituent groups, and the terms “heteroatom-containing alkyl” and“heteroalkyl” refer to alkyl groups in which at least one carbon atom isreplaced with a heteroatom. If not otherwise indicated, the terms“alkyl” and “lower alkyl” include linear, branched, cyclic,unsubstituted, substituted, and/or heteroatom-containing alkyl and loweralkyl groups, respectively.

The term “alkylene” as used herein refers to a difunctional linear,branched, or cyclic alkyl group, where “alkyl” is as defined above.

The term “alkenyl” as used herein refers to a linear, branched, orcyclic hydrocarbon group of 2 to about 24 carbon atoms containing atleast one double bond, such as ethenyl, n-propenyl, isopropenyl,n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl,eicosenyl, tetracosenyl, and the like. Preferred alkenyl groups hereincontain 2 to about 12 carbon atoms. The term “lower alkenyl” intends analkenyl group of 2 to 6 carbon atoms, and the specific term“cycloalkenyl” intends a cyclic alkenyl group, preferably having 5 to 8carbon atoms. The term “substituted alkenyl” refers to alkenyl groupssubstituted with one or more substituent groups, and the terms“heteroatom-containing alkenyl” and “heteroalkenyl” refer to alkenylgroups in which at least one carbon atom is replaced with a heteroatom.If not otherwise indicated, the terms “alkenyl” and “lower alkenyl”include linear, branched, cyclic, unsubstituted, substituted, and/orheteroatom-containing alkenyl and lower alkenyl groups, respectively.

The term “alkenylene” as used herein refers to a difunctional linear,branched, or cyclic alkenyl group, where “alkenyl” is as defined above.

The term “alkynyl” as used herein refers to a linear or branchedhydrocarbon group of 2 to about 24 carbon atoms containing at least onetriple bond, such as ethynyl, n-propynyl, and the like. Preferredalkynyl groups herein contain 2 to about 12 carbon atoms. The term“lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms. Theterm “substituted alkynyl” refers to an alkynyl group substituted withone or more substituent groups, and the terms “heteroatom-containingalkynyl” and “heteroalkynyl” refer to alkynyl in which at least onecarbon atom is replaced with a heteroatom. If not otherwise indicated,the terms “alkynyl” and “lower alkynyl” include a linear, branched,unsubstituted, substituted, and/or heteroatom-containing alkynyl andlower alkynyl group, respectively.

The term “alkoxy” as used herein intends an alkyl group bound through asingle, terminal ether linkage; that is, an “alkoxy” group may berepresented as —O-alkyl where alkyl is as defined above. A “loweralkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms.Analogously, “alkenyloxy” and “lower alkenyloxy” respectively refer toan alkenyl and lower alkenyl group bound through a single, terminalether linkage, and “alkynyloxy” and “lower alkynyloxy” respectivelyrefer to an alkynyl and lower alkynyl group bound through a single,terminal ether linkage.

The term “aromatic” refers to the ring moieties which satisfy the Hückel4n+2 rule for aromaticity, and includes both aryl (i.e., carbocyclic)and heteroaryl (also called heteroaromatic) structures, including aryl,aralkyl, alkaryl, heteroaryl, heteroaralkyl, or alk-heteroaryl moieties,or pre-polymeric (e.g., monomeric, dimeric), oligomeric or polymericanalogs thereof. While the descriptions of the methods and systemsinvolving KOH are provided in terms of heteroaromatic substrates, wheretheir operability is preferred, it is reasonably believed that they alsowork on aryl substrates.

The term “aryl” as used herein, and unless otherwise specified, refersto an aromatic substituent or structure containing a single aromaticring or multiple aromatic rings that are fused together, directlylinked, or indirectly linked (such that the different aromatic rings arebound to a common group such as a methylene or ethylene moiety). Unlessotherwise modified, the term “aryl” refers to carbocyclic structures.Preferred aryl groups contain 5 to 24 carbon atoms, and particularlypreferred aryl groups contain 5 to 14 carbon atoms. Exemplary arylgroups contain one aromatic ring or two fused or linked aromatic rings,e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine,benzophenone, and the like. “Substituted aryl” refers to an aryl moietysubstituted with one or more substituent groups, and the terms“heteroatom-containing aryl” and “heteroaryl” refer to aryl substituentsin which at least one carbon atom is replaced with a heteroatom, as willbe described in further detail infra.

The term “aryloxy” as used herein refers to an aryl group bound througha single, terminal ether linkage, wherein “aryl” is as defined above. An“aryloxy” group may be represented as —O-aryl where aryl is as definedabove. Preferred aryloxy groups contain 5 to 24 carbon atoms, andparticularly preferred aryloxy groups contain 5 to 14 carbon atoms.Examples of aryloxy groups include, without limitation, phenoxy,o-halo-phenoxy, m-halo-phenoxy, p-halo-phenoxy, o-methoxy-phenoxy,m-methoxy-phenoxy, p-methoxy-phenoxy, 2,4-dimethoxy-phenoxy,3,4,5-trimethoxy-phenoxy, and the like.

The term “alkaryl” refers to an aryl group with an alkyl substituent,and the term “aralkyl” refers to an alkyl group with an arylsubstituent, wherein “aryl” and “alkyl” are as defined above. Preferredalkaryl and aralkyl groups contain 6 to 24 carbon atoms, andparticularly preferred alkaryl and aralkyl groups contain 6 to 16 carbonatoms. Alkaryl groups include, for example, p-methylphenyl,2,4-dimethylphenyl, p-cyclohexylphenyl, 2, 7-dimethylnaphthyl,7-cyclooctylnaphthyl, 3-ethyl-cyclopenta-1,4-diene, and the like.Examples of aralkyl groups include, without limitation, benzyl,2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl,4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl,4-benzylcyclohexylmethyl, and the like. The terms “alkaryloxy” and“aralkyloxy” refer to substituents of the formula —OR wherein R isalkaryl or aralkyl, respectively, as just defined.

The term “acyl” refers to substituents having the formula —(CO)-alkyl,—(CO)-aryl, or —(CO)-aralkyl, and the term “acyloxy” refers tosubstituents having the formula —O(CO)-alkyl, —O(CO)-aryl, or—O(CO)-aralkyl, wherein “alkyl,” “aryl, and “aralkyl” are as definedabove.

The terms “cyclic” and “ring” refer to alicyclic or aromatic groups thatmay or may not be substituted and/or heteroatom-containing, and that maybe monocyclic, bicyclic, or polycyclic. The term “alicyclic” is used inthe conventional sense to refer to an aliphatic cyclic moiety, asopposed to an aromatic cyclic moiety, and may be monocyclic, bicyclic,or polycyclic. The term “acyclic” refers to a structure in which thedouble bond is not contained within a ring structure.

The terms “halo,” “halide,” and “halogen” are used in the conventionalsense to refer to a chloro, bromo, fluoro, or iodo substituent.

“Hydrocarbyl” refers to univalent hydrocarbyl radicals containing 1 toabout 30 carbon atoms, preferably 1 to about 24 carbon atoms, mostpreferably 1 to about 12 carbon atoms, including linear, branched,cyclic, saturated, and unsaturated species, such as alkyl groups,alkenyl groups, aryl groups, and the like. The term “lower hydrocarbyl”intends a hydrocarbyl group of 1 to 6 carbon atoms, preferably 1 to 4carbon atoms, and the term “hydrocarbylene” intends a divalenthydrocarbyl moiety containing 1 to about 30 carbon atoms, preferably 1to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms,including linear, branched, cyclic, saturated and unsaturated species.The term “lower hydrocarbylene” intends a hydrocarbylene group of 1 to 6carbon atoms. “Substituted hydrocarbyl” refers to hydrocarbylsubstituted with one or more substituent groups, and the terms“heteroatom-containing hydrocarbyl” and “heterohydrocarbyl” refer tohydrocarbyl in which at least one carbon atom is replaced with aheteroatom. Similarly, “substituted hydrocarbylene” refers tohydrocarbylene substituted with one or more substituent groups, and theterms “heteroatom-containing hydrocarbylene” and heterohydrocarbylene”refer to hydrocarbylene in which at least one carbon atom is replacedwith a heteroatom. Unless otherwise indicated, the term “hydrocarbyl”and “hydrocarbylene” are to be interpreted as including substitutedand/or heteroatom-containing hydrocarbyl and hydrocarbylene moieties,respectively.

The term “heteroatom-containing” as in a “heteroatom-containinghydrocarbyl group” refers to a hydrocarbon molecule or a hydrocarbylmolecular fragment in which one or more carbon atoms is replaced with anatom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus orsilicon, typically nitrogen, oxygen or sulfur. Similarly, the term“heteroalkyl” refers to an alkyl substituent that isheteroatom-containing, the term “heterocyclic” refers to a cyclicsubstituent that is heteroatom-containing, the terms “heteroaryl” andheteroaromatic” respectively refer to “aryl” and “aromatic” substituentsthat are heteroatom-containing, and the like. It should be noted that a“heterocyclic” group or compound may or may not be aromatic, and furtherthat “heterocycles” may be monocyclic, bicyclic, or polycyclic asdescribed above with respect to the term “aryl.” Examples of heteroalkylgroups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylatedamino alkyl, and the like. Non-limiting examples of heteroarylsubstituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl,indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., andexamples of heteroatom-containing alicyclic groups are pyrrolidino,morpholino, piperazino, piperidino, etc.

As used herein, the terms “substrate” or “organic substrate” areintended to connote both discrete small molecules (sometimes describedas “organic compounds”) and oligomers and polymers containing such“aromatic moieties.” The term “aromatic moieties” is intended to referto those portions of the compounds, pre-polymers (i.e., monomericcompounds capable of polymerizing), oligomers, or polymers having atleast one of the indicated aromatic structure. Where shown asstructures, the moieties contain at least that which is shown, as wellas containing further functionalization, substituents, or both,including but not limited to the functionalization described as “Fn”herein.

By “substituted” as in “substituted hydrocarbyl,” “substituted alkyl,”“substituted aryl,” and the like, as alluded to in some of theaforementioned definitions, is meant that in the hydrocarbyl, alkyl,aryl, heteroaryl, or other moiety, at least one hydrogen atom bound to acarbon (or other) atom is replaced with one or more non-hydrogensubstituents. Examples of such substituents include, without limitation:functional groups referred to herein as “Fn,” such as halo (e.g., F, Cl,Br, I), hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄alkynyloxy, C₅-C₂₄ aryloxy, C₆-C₂₄ aralkyloxy, C₆-C₂₄ alkaryloxy, acyl(including C₁-C₂₄ alkylcarbonyl (—CO-alkyl) and C₆-C₂₄ arylcarbonyl(—CO-aryl)), acyloxy (—O-acyl, including C₂-C₂₄ alkylcarbonyloxy(—O—CO-alkyl) and C₆-C₂₄ arylcarbonyloxy (—O—CO-aryl)), C₂-C₂₄alkoxycarbonyl ((CO)—O-alkyl), C₆-C₂₄ aryloxycarbonyl (—(CO)—O-aryl),halocarbonyl (—CO)—X where X is halo), C₂-C₂₄ alkylcarbonato(—O—(CO)—O-alkyl), C₆-C₂₄ arylcarbonato (—O—(CO)—O-aryl), carboxy(—COOH), carboxylato (—COO—), carbamoyl (—(CO)—NH₂), mono-(C₁-C₂₄alkyl)-substituted carbamoyl (—(CO)NH(C₁-C₂₄ alkyl)), di-(C₁-C₂₄alkyl)-substituted carbamoyl (—(CO)—N(C₁-C₂₄ alkyl)₂), mono-(C₁-C₂₄haloalkyl)-substituted carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), di-(C₁-C₂₄haloalkyl)-substituted carbamoyl (—(CO)—N(C₁-C₂₄ alkyl)₂), mono-(C₅-C₂₄aryl)-substituted carbamoyl (—(CO)—NH-aryl), di-(C₅-C₂₄ aryl)substitutedcarbamoyl (—(CO)—N(C₅-C₂₄ aryl)₂), di-N—(C₁-C₂₄ alkyl),N—(C₅-C₂₄aryl)-substituted carbamoyl, thiocarbamoyl (—(CS)—NH₂), mono-(C₁-C₂₄alkyl)-substituted thiocarbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl (—(CO)—N(C₁-C₂₄ alkyl)₂), mono-(C₅-C₂₄aryl)substituted thiocarbamoyl (—(CO)—NH-aryl), di-(C₅-C₂₄aryl)-substituted thiocarbamoyl (—(CO)—N(C₅-C₂₄ aryl)₂), di-N—(C₁-C₂₄alkyl),N—(C₅-C₂₄ aryl)-substituted thiocarbamoyl, carbamido(—NH—(CO)—NH₂), cyano(—C≡N), cyanato (—O—C═N), thiocyanato (—S—C═N),formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), mono-(C₁-C₂₄alkyl)-substituted amino, di-(C₁-C₂₄ alkyl)-substituted amino,mono-(C₅-C₂₄ aryl)substituted amino, di-(C₅-C₂₄ aryl)-substituted amino,C₁-C₂₄ alkylamido (—NH—(CO)-alkyl), C₆-C₂₄ arylamido (—NH—(CO)-aryl),imino (—CR═NH where R=hydrogen, C₁-C₂₄ alkyl, C₅-C₂₄ aryl, C₆-C₂₄alkaryl, C₆-C₂₄ aralkyl, etc.), C₂-C₂₀ alkylimino (—CR═N(alkyl), whereR=hydrogen, C₁-C₂₄ alkyl, C₅-C₂₄ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl,etc.), arylimino (—CR═N(aryl), where R=hydrogen, C₁-C₂₀ alkyl, C₅-C₂₄aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.), nitro (—NO₂), nitroso(—NO), sulfo (—SO₂OH), sulfonate(SO₂O—), C₁-C₂₄ alkylsulfanyl (—S-alkyl;also termed “alkylthio”), C₅-C₂₄ arylsulfanyl (—S-aryl; also termed“arylthio”), C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl), C₅-C₂₄ arylsulfinyl(—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl), C₁-C₂₄monoalkylaminosulfonyl-SO₂—N(H) alkyl), C₁-C₂₄dialkylaminosulfonyl-SO₂—N(alkyl)₂, C₅-C₂₄ arylsulfonyl (—SO₂-aryl),boryl (—BH₂), borono (—B(OH)₂), boronato (—B(OR)₂ where R is alkyl orother hydrocarbyl), phosphono (—P(O)(OH)₂), phosphonato (—P(O)(O)₂),phosphinato (P(O)(O—)), phospho (—PO₂), and phosphine (—PH₂); and thehydrocarbyl moieties C₁-C₂₄ alkyl (preferably C₁-C₁₂ alkyl, morepreferably C₁-C₆ alkyl), C₂-C₂₄ alkenyl (preferably C₂-C₁₂ alkenyl, morepreferably C₂-C₆ alkenyl), C₂-C₂₄ alkynyl (preferably C₂-C₁₂ alkynyl,more preferably C₂-C₆ alkynyl), C₅-C₂₄ aryl (preferably C₅-C₂₄ aryl),C₆-C₂₄ alkaryl (preferably C₆-C₁₆ alkaryl), and C₆-C₂₄ aralkyl(preferably C₆-C₁₆ aralkyl). Within these substituent structures, the“alkyl,” “alkylene,” “alkenyl,” “alkenylene,” “alkynyl,” “alkynylene,”“alkoxy,” “aromatic,” “aryl,” “aryloxy,” “alkaryl,” and “aralkyl”moieties may be optionally fluorinated or perfluorinated. Additionally,reference to alcohols, aldehydes, amines, carboxylic acids, ketones, orother similarly reactive functional groups also includes their protectedanalogs. For example, reference to hydroxy or alcohol also includesthose substituents wherein the hydroxy is protected by acetyl (Ac),benzoyl (Bz), benzyl (Bn, Bnl), β-Methoxyethoxymethyl ether (MEM),dimethoxytrityl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT),methoxymethyl ether (MOM), methoxytrityl[(4-methoxyphenyl)diphenylmethyl, MMT), p-methoxybenzyl ether (PMB),methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP),tetrahydrofuran (THF), trityl (triphenylmethyl, Tr), silyl ether (mostpopular ones include trimethylsilyl (TMS), tert-butyldimethylsilyl(TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl(TIPS) ethers), ethoxyethyl ethers (EE). Reference to amines alsoincludes those substituents wherein the amine is protected by a BOCglycine, carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ),tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl(Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB),3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts) group, orsulfonamide (Nosyl & Nps) group. Reference to substituent containing acarbonyl group also includes those substituents wherein the carbonyl isprotected by an acetal or ketal, acylal, or diathane group. Reference tosubstituent containing a carboxylic acid or carboxylate group alsoincludes those substituents wherein the carboxylic acid or carboxylategroup is protected by its methyl ester, benzyl ester, tert-butyl ester,an ester of 2,6-disubstituted phenol (e.g. 2,6-dimethylphenol,2,6-diisopropylphenol, 2,6-di-tert-butylphenol), a silyl ester, anorthoester, or an oxazoline. Preferred substituents are those identifiedherein as not or less affecting the silylation chemistries, for example,including those substituents comprising alkyls; alkoxides, aryloxides,aralkylalkoxides, protected carbonyl groups; aryls optionallysubstituted with F, Cl, —CF₃; epoxides; N-alkyl aziridines; cis- andtrans-olefins; acetylenes; pyridines, primary, secondary and tertiaryamines; phosphines; and hydroxides.

By “functionalized” as in “functionalized hydrocarbyl,” “functionalizedalkyl,” “functionalized olefin,” “functionalized cyclic olefin,” and thelike, is meant that in the hydrocarbyl, alkyl, aryl, heteroaryl, olefin,cyclic olefin, or other moiety, at least one hydrogen atom bound to acarbon (or other) atom is replaced with one or more functional groupssuch as those described herein and above. The term “functional group” ismeant to include any functional species that is suitable for the usesdescribed herein. In particular, as used herein, a functional groupwould necessarily possess the ability to react with or bond tocorresponding functional groups on a substrate surface.

In addition, the aforementioned functional groups may, if a particulargroup permits, be further substituted with one or more additionalfunctional groups or with one or more hydrocarbyl moieties such as thosespecifically enumerated above. Analogously, the above-mentionedhydrocarbyl moieties may be further substituted with one or morefunctional groups or additional hydrocarbyl moieties such as thosespecifically enumerated.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.For example, the phrase “optionally substituted” means that anon-hydrogen substituent may or may not be present on a given atom, and,thus, the description includes structures wherein a non-hydrogensubstituent is present and structures wherein a non-hydrogen substituentis not present.

As used herein, the term “silylating” refers to the forming ofcarbon-silicon bonds, in a position previously occupied by acarbon-hydrogen bond, generally a non-activated C—H bond. The ability toreplace directly a C—H bond with a C—Si bond, under the conditionsdescribed herein, is believed to be unprecedented.

The present invention includes embodiments related chemical systems andmethods for silylating aromatic compounds and aromatic moieties.Specific embodiments provide chemical systems for silylating aromaticcompounds and aromatic moieties, each system comprising a mixture of (a)at least one organosilane and (b) at least one strong base, thedefinition of said strong base now also including hydroxide, especiallyKOH, said system being preferably, but not necessarily, substantiallyfree of a transition-metal compound.

It is recognized that the systems and reactions which provide for thesilylation of aromatic compounds and aromatic moieties, under differentconditions (mainly at higher temperatures), are also capable of cleavingC—O, C—N, C—S bonds within aromatic substrates. This latter reductivecleavage feature is the subject of a co-pending U.S. patent applicationSer. No. 14/043,917, filed Oct. 2, 2013, entitled “Transition-Metal-FreeReductive Cleavage of Aromatic C—O, C—N, and C—S Bonds by ActivatedSilanes” which is also incorporated by reference in its entirety for allpurposes. The mechanism by which the system and methods operate is notyet understood, for example, whether the silylation is an intermediatestep or a co-product or by-product of the cleavage reactions (certainobservations suggest not), but it does appear that the relativecontribution of each manifold can be manipulated by the reactionconditions. For example, other factors being similar or equal and withcertain exceptions, it appears that higher temperatures and longerreaction times tend favor the cleavage of C—O, C—N, C—S bonds over thesilylation reactions (which occur at relatively milder temperatures).Similarly, absence of hydrogen and hydrogen donor molecules (even at thehigher temperatures) and use of sub-stoichiometric quantities of thestrong base, the definition of said strong base now also includinghydroxide, especially KOH (relative to the organosilane) appear to favorthe silylation reactions and disfavor the C—X cleavages.

Preliminary mechanistic investigations for at least the silylation ofheteroaromatics suggest the involvement of radical species, though acontinuum of mechanism may be operable. An elementary silyl radicalgeneration-substitution mechanism seems to be unlikely owing to poorreactivity with electron deficient heteroarenes, such as pyridine (e.g.,Example 6.9.49 to 51). Moreover, the rate of silylation was greater insulphur-containing heteroarenes than in oxygen-containing heteroarenes,and was greater in oxygen-containing heteroarenes than innitrogen-containing heteroarenes, as observed in an internal competitionstudy (see, e.g., Example 7.1), which provided complementary reactivityto electrophilic substitutions and Minisci-type reactions. Theseobservations pointed to an underlying mechanism that is distinct fromknown heteroaromatic C—H functionalization reactions.

As used herein, the term “substantially free of a transition-metalcompound” is intended to reflect that the system is effective for itsintended purpose of silylating aromatic compounds and aromatic moietiesunder the relatively mild conditions described herein, even in theabsence of any exogenous (i.e., deliberately added or otherwise)transition-metal catalyst(s). While certain embodiments provide thattransition metals, including those capable of catalyzing silylationreactions, may be present within the systems or methods described hereinat levels normally associated with such catalytic activity, the presenceof such metals (either as catalysts or spectator compounds) is notrequired and in many cases is not desirable. As such, in preferredembodiments, the system and methods are “substantially free oftransition-metal compounds.” Unless otherwise stated, then, the term“substantially free of a transition-metal compound” is defined toreflect that the total level of transition metal within the silylatingsystem, independently or in the presence of organic substrate, is lessthan about 5 ppm, as measured by ICP-MS as described in Example 3.3below. Additional embodiments also provide that the concentration oftransition metals is less than about 10 wt %, 5 wt %, 1 wt %, 100 ppm,50 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, or 5 ppm to about 1 ppmor 0 ppm. As used herein, the term “transition metal” is defined toinclude Co, Rh, Ir, Fe, Ru, Os, Ni, Pd, Pt, Cu, or combinations thereof.In further specific independent embodiments, the concentration of Ni, asmeasured by ICP-MS, is less than 25 ppm, less than 10 ppm, less than 5ppm, or less than 1 ppm.

These systems typically comprise hydrocarbon or ether-based solvents, orthe systems can be operated without solvent. As described herein,solvents such as benzene, toluene, mesitylene, and tetrahydrofurans(including 2-methyltetrahydrofuran) have been shown to work well. Incertain embodiments, the reactions are done in neat substrates.

While it may not be necessary to limit the system's exposure to waterand oxygen, in some embodiments, the chemical systems and the methodsare done in an environment substantially free of water, oxygen, or bothwater and oxygen. In other embodiments, air and/or water are present.Unless otherwise specified, the term “substantially free of water”refers to levels of water less than about 500 ppm and “substantiallyfree of oxygen” refers to oxygen levels corresponding to partialpressures less than 1 torr. Where stated, additional independentembodiments may provide that “substantially free of water” refers tolevels of water less than 1.5%, 1%, 0.5%, 1000 ppm, 500 ppm, 250 ppm,100 ppm, 50 ppm, 10 ppm, or 1 ppm and “substantially free of oxygen”refers to oxygen levels corresponding to partial pressures less than 50torr, 10 torr, 5 torr, 1 torr, 500 millitorr, 250 millitorr, 100millitorr, 50 millitorr, or 10 millitorr. In the General Proceduredescribed herein, deliberate efforts were made to exclude both water andoxygen, unless otherwise specified.

As used herein to describe the systems and methods, the terms“organosilane” or “hydrosilane” may be used interchangeably and refer toa compound or reagent having at least one silicon-hydrogen (Si—H) bond.The organosilane may further contain a silicon-carbon, a silicon-oxygen,a silicon-nitrogen bond, or a combination thereof, and may be monomeric,or contained within an oligomeric or polymeric framework, includingbeing tethered to a heterogeneous or homogeneous support structure. Incertain embodiments, these organosilane may comprise at least onecompound of Formula (I) or Formula (II):(R)_(4-m)Si(H)_(m)  (I)R—[—SiH(R)—O—]_(n)—R  (II)where: m is 1, 2, or 3, preferably 1 or 2;

n is in a range of from about 5 to about 500, from about 10 to about 100or from about 25 to about 50; and

each R is independently optionally substituted C₁₋₁₂ alkyl orheteroalkyl, optionally substituted C₅₋₂₀ aryl or C₄₋₂₀ heteroaryl,optionally substituted C₆₋₃₀ alkaryl or C₄₋₃₀ heteroalkaryl, optionallysubstituted C₆₋₃₀ aralkyl or C₄₋₃₀ heteroaralkyl, optionally substituted—O—C₁₋₁₂ alkyl or heteroalkyl, optionally substituted —O—C₅₋₂₀ aryl or—O—C₄₋₂₀ heteroaryl, optionally substituted —O—C₆₋₃₀ alkaryl or —O—C₄₋₃₀heteroalkaryl, or optionally substituted —O—C₆₋₃₀ aralkyl or —O—C₄₋₃₀heteroaralkyl, and, if substituted, the substituents may be phosphonato,phosphoryl, phosphanyl, phosphino, sulfonato, C₁-C₂₀ alkylsulfanyl,C₅-C₂₀ arylsulfanyl, C₁-C₂₀ alkylsulfonyl, C₅-C₂₀ arylsulfonyl, C₁-C₂₀alkylsulfinyl, C₅-C₂₀ arylsulfinyl, sulfonamido, amino, amido, imino,nitro, nitroso, hydroxyl, C₁-C₂₀ alkoxy, C₅-C₂₀ aryloxy, C₂-C₂₀alkoxycarbonyl, C₅-C₂₀ aryloxycarbonyl, carboxyl, carboxylato, mercapto,formyl, C₁-C₂₀ thioester, cyano, cyanato, thiocyanato, isocyanate,thioisocyanate, carbamoyl, epoxy, styrenyl, silyl, silyloxy, silanyl,siloxazanyl, boronato, boryl, or halogen, or a metal-containing ormetalloid-containing group, where the metalloid is Sn or Ge, where thesubstituents may optionally provide a tether to an insoluble orsparingly soluble support media comprising alumina, silica, or carbon.Exemplary, non-limiting organosilanes include (R)₃SiH, where R is C₁₋₆alkyl, particularly triethylsilane and tributylsilane, mixed aryl alkylsilanes, such as PhMe₂SiH, and polymeric materials, such aspolymethylhydrosiloxane (PMHS). The use of organosilanes of generalstructure (R)₂SiH₂ also work well, and provide for opportunities forcoupling or bridging reactions.

As used herein, the term “strong base” refers to a compound having astrong affinity for hydrogen atoms especially, but not only, innon-aqueous media. In specific independent embodiments, the at least onestrong base comprises an alkali or alkaline metal hydride or alkoxide.It should be appreciated, then, that this definition is not strictlylimited to the classic conjugate acid-base model—since the conjugateacid of hydride would be dihydrogen. One measure of this “strongaffinity” may be that the strong base, if reacted with water, wouldreact to the practically complete formation of hydroxide therefrom.Other “strong bases” may be considered as including alkyl lithiumcompounds or amide ions, for example potassium bis(trimethylsilyl)amide. Again, these descriptions have previously been used to describealkoxide, alkyl (e.g., alkyl lithium compounds), amide ions, hydrides,and other extremely strong bases. In the context of previousdisclosures, these descriptions were used in context of materialsdescribed as “superbases.” It is now discovered that the term “strongbase” may also be considered to encompass hydroxides, particularly KOH(potassium hydroxide), within the scope of this invention.

Useful alkoxides include those comprising a C₁₋₁₂ linear or branchedalkyl moietird or a C₅₋₁₀ aromatic or C₄₋₁₀ heteroaromatic moieties, forexamples methoxide, ethoxide, propoxide, butoxide, 2-ethyl-hexyloxide,or benzyloxide. Each of these appears to give comparable reactivity.Further, the choice of the counter cation also impacts the effectivenessof the activity of the chemical system, such that potassium ispreferred. More specifically, potassium methoxide, ethoxide, andtert-butoxide and cesium 2-ethyl-hexyl alkoxide have been shown to beeffective in this role. By comparison, the reaction of Et₃SiH withlithium or sodium tert-butoxide provides little or no reactivitysuggesting that the counter ion plays a critical role in the generationof the active silylating species and, possibly, in activation of thesubstrate ether, or both. Similarly, conducting reactions with potassiumtert-butoxide in the presence of sufficient 18-crown-6 to act as apotassium chelator resulted in nearly complete inhibition of thereaction.

Hydroxides such as potassium hydroxide (KOH) are now, for the firsttime, considered to be useful sources of base in the inventive methods.The hydroxide, KOH, may be formed in situ, for example by the reactionof metallic metal (e.g., potassium) with water, but in preferredembodiments, the hydroxide (e.g., KOH) is deliberately added as such,and preferably anhydrously (i.e., in the absence of water). It does notappear that the conditions of the reactions previously describedgenerated sufficient KOH for it to work in this capacity.

While the relative amounts of organosilane and strong base, thedefinition of said strong base now also including hydroxide, especiallyKOH, is not believed to be particularly important, so long as both arepresent in sufficient quantities, in certain embodiments, theorganosilane and the at least one strong base, the definition of saidstrong base now also including hydroxide, especially KOH, are presenttogether at a molar ratio, with respect to one another, in a range offrom about 20:1 to about 1:1. In other embodiments, these ratios may beon the order of about 5:1 to about 1:1, from about 3:1 to about 1:1, orfrom about 3:2 to about 1:1. The silylation reactions appear also tofavor those conditions where the base is sub-stoichiometric, 0.01:1 to0.9:1, with respect to the substrate, especially for more activesystems. Further embodiments provide that the base is present withrespect to the substrate at a ratio of from about 0.01:1 to about 0.6,or from about 0.1:1 to about 0.6. See, e.g., Table 6.

Further embodiments provide systems further comprising N-based compounds(preferably N-based chelants) including, for example, optionallysubstituted tetraalkylethylenediamine (e.g.,tetramethylethylenediamine), optionally substituted 1,10-phenanthrolinederivatives, optionally substituted 2,2′-bipyridine derivatives, andoptionally substituted 4-dimethylaminopyridine derivatives. See, e.g.,Example 2 and Table 2.

To this point, the invention has been described in terms of the chemicalsystem capable of silylating aromatic compounds or moieties, but itshould also be apparent that the invention also includes the methods ofcarrying out these transformations. That is, various additionalembodiments include those methods where an organic substrate comprisingan aromatic moiety is contacted with any of the chemical systemsdescribed above under conditions sufficient to silylate at least aportion of the substrate. That is, certain embodiments provide methods,each method comprising contacting an organic substrate comprising anaromatic moiety with a mixture of (a) at least one organosilane and (b)at least one strong base, the definition of said strong base now alsoincluding hydroxide, especially KOH, under conditions sufficient tosilylate the substrate; wherein said mixture and substrate arepreferably, but not necessarily, substantially free of atransition-metal compound. These embodiments are generally done in theliquid phase, without UV irradiation or electric or plasma dischargeconditions.

In some embodiments, the conditions sufficient to silylate the organicsubstrate comprise heating the substrate with a mixture of (a) the atleast one organosilane and (b) the at least one strong base, thedefinition of said strong base now also including hydroxide, especiallyKOH, at a temperature in a range of about 10° C. to about 165° C. Insome cases, the temperatures may be applied in a range of from about 20°C., about 30° C., about 40° C., about 50° C., about 60° C., or about 80°C. to about 165° C., about 150° C., about 125° C., about 100° C., or toabout 80° C. Any of the temperatures described in the Examples may beconsidered independent embodiments. Typical operating reaction times mayrange from about 2 hours, from about 4 hours, from about 6 hours, orfrom about 10 hours to about 28 days, to about 14 days, to about 7 days,to about 4 days, to about 3 days, to about 48 hours, to about 24 hours,to about 12 hours, or to about 6 hours.

As described above, those features described as relevant for thechemical systems for silylating aromatic compounds and aromatic moietiesare also relevant for the methods of silylating these aromatic compoundsand aromatic moieties. For example, in various embodiments, the methodsprovide that the system is substantially free of water, oxygen, or bothwater and oxygen.

In other embodiments, at least one organosilane comprises anorganosilane of Formula (I) or Formula (II):(R)_(4-m)Si(H)_(m)  (I)R—[—SiH(R)—O—]_(n)—R  (II)where m is 1, 2, or 3 (preferably 1 or 2);

n is 10 to 100; and

each R is independently optionally substituted C₁₋₁₂ alkyl orheteroalkyl, optionally substituted C₅₋₂₀ aryl or C₄₋₂₀ heteroaryl,optionally substituted C₆₋₃₀ alkaryl or C₄₋₃₀ heteroalkaryl, optionallysubstituted C₆₋₃₀ aralkyl or heteroaralkyl, optionally substituted—O—C₁₋₁₂ alkyl or heteroalkyl, optionally substituted —O—C₅₋₂₀ aryl or—O—C₄₋₂₀ heteroaryl, optionally substituted —O—C₆₋₃₀ alkaryl or C₄₋₃₀heteroalkaryl, or optionally substituted —O—C₆₋₃₀ aralkyl or —O—C₄₋₃₀heteroaralkyl, and, if substituted, the substituents may be phosphonato,phosphoryl, phosphanyl, phosphino, sulfonato, C₁-C₂₀ alkylsulfanyl,C₅-C₂₀ arylsulfanyl, C₁-C₂₀ alkylsulfonyl, C₅-C₂₀ arylsulfonyl, C₁-C₂₀alkylsulfinyl, C₅-C₂₀ arylsulfinyl, sulfonamido, amino, amido, imino,nitro, nitroso, hydroxyl, C₁-C₂₀ alkoxy, C₅-C₂₀ aryloxy, C₂-C₂₀alkoxycarbonyl, C₅-C₂₀ aryloxycarbonyl, carboxyl, carboxylato, mercapto,formyl, C₁-C₂₀ thioester, cyano, cyanato, thiocyanato, isocyanate,thioisocyanate, carbamoyl, epoxy, styrenyl, silyl, silyloxy, silanyl,siloxazanyl, boronato, boryl, or halogen, or a metal-containing ormetalloid-containing group, where the metalloid is Sn or Ge, where thesubstituents may optionally provide a tether to an insoluble orsparingly soluble support media comprising alumina, silica, or carbon.

In still other embodiments, the organosilane is (R)₃SiH, where R is C₁₋₆alkyl, preferably Et₃SiH or Et₂MeSiH, or (R)₂SiH₂. The at least onestrong base may comprise an alkali or alkaline metal hydride, asdescribed above, for example, calcium hydride or potassium hydride. Theat least one strong base may comprise an alkali or alkaline metalalkoxide, as described above, for example, where the at least onealkoxide comprises a C₁₋₁₂ linear or branched alkyl moiety or a C₅₋₁₀aryl or C₄₋₁₀ heteroaryl moiety, preferably methoxide, ethoxide,propoxide, butoxide, or 2-ethyl-hexyl alkoxide. The alkali metal cationis preferably potassium or cesium. In most preferred embodiments, theorganosilane is triethylsilane, trimethyl silane, diethylmethylsilane,diethylsilane, dimethylsilane, dimethylethylsilane, ethyldimethylsilane,dimethylphenylsilane, diethylphenylsilane and the strong base ispotassium tert-butoxide. The strong base may now include potassiumhydroxide. Other combinations or exemplified reactants provideadditional embodiments in this regard.

In certain embodiments, the organosilane (or monomer equivalent) and theat least one strong base, the definition of said strong base now alsoincluding hydroxide, especially KOH, are present together at a molarratio, with respect to one another, in a range of from about 20:1 toabout 1:1. In certain embodiments the at least one strong base,including KOH, and organic substrate are present together at a molarratio, with respect to one another, in a range of from about 0.01:1 toabout 5:1. Preferably the base is sub-stoichiometric—i.e., in a ratio of0.01:1 to 0.9:1—with respect to the organic substrate. That is, themethods may be considered to be catalytic with respect to the basescontemplated herein.

Additionally, in the context of the methods, the term “substantiallyfree of a transition-metal compound” carries the same connotations andrelated embodiments as described supra for the chemical system; i.e.,reflecting that the methods are effectively conducted in the absence ofany deliberately added transition-metal catalyst(s). Unless otherwisestated, when describing a method or system, the term is defined toreflect that the total level of transition metal, as measured by ICP-MSas described in Example 3.3 below, is less than about 50 ppm. Additionalembodiments also provide that the concentration of transition metals isless than about 10 wt %, 5 wt %, 1 wt %, 100 ppm, 50 ppm, 30 ppm, 25ppm, 20 ppm, 15 ppm, 10 ppm, or 5 ppm to about 1 ppm or 0 ppm, relativeto the weight of the total system (i.e., both respect to the silylationsystem and the silylation system and the organic substrate). As usedherein, the term “transition metal” is defined at least to include Co,Rh, Ir, Fe, Ru, Os, Ni, Pd, Pt, Cu, or combinations thereof. In furtherindependent embodiments, the concentration of Ni, as measured by ICP-MS,is less than 25 ppm, less than 10 ppm, less than 5 ppm, or less than 1ppm. Noting here that certain embodiments of the chemical system maycomprise the at least one organosilane, and strong base, the definitionof said strong base now also including hydroxide, especially KOH, itshould be appreciated that independent embodiments provide that thelevels of transition metals are maintained below the levels justdescribed, when considering each of these mixture combinations.

Further embodiments provide that the methods further comprise usingsub-stoichiometric amounts (relative to the substrate) of N-basedcompounds including (preferably N-based chelants), for example,optionally substituted tetraalkylethylenediamine (e.g.,tetramethylethylenediamine), optionally substituted 1,7-phenanthrolinederivatives, optionally substituted 1,10-phenanthroline derivatives,optionally substituted 2,2′-bipyridine derivatives, and optionallysubstituted 4-dimethylaminopyridine derivatives.

The methods are fairly flexible with respect to substrates, andaccommodate both those containing both aryl and heteroaryl moieties.Exemplary substrates comprising aryl moieties include those comprisingoptionally substituted benzene (including mesitylene and toluene),biphenyl, naphthalene, anthracene, or higher polyaromatic ringstructures. These pure hydrocarbon substrates generally require moreforcing conditions to silylate the ring carbons than do heteroarylsystems. See Example 6.4. Nevertheless, the ability to functionalizethese hydrocarbon ring structures is an important feature of thesemethods and systems.

Where the aryl or heteroaryl moiety comprises an alpha-methyl ormethylene C—H bond, as in an optionally substituted C₁₋₆ alkyl group (asexemplified by methyl groups of toluene, mesitylene, 1,2 dimethylindole,or 2,5-dimethylthiophene in the Examples), it appears that the reactionproceeds to form alpha silanes at temperatures lowered than required tosilylate the ring carbons. As used herein, the term “alpha carbon”refers to the first carbon positioned exocyclic to the aromatic moeity,and “alpha” as in “alpha methyl or methylene” is intended to refer tothe methyl or methylene on the first exocyckic carbon directly attachedto the aromatic ring. The term “alpha silane” refers a silane bonded tothe alpha carbon. The term “alpha” is considered to encompass benzyliccarbons for 6 membered aryl aromatics. Methods resulting in suchsilylations are within the scope of the present invention.

Other exocyclic ring substituents, including those having an exocyclicaromatic C—X bond, generally react according to the methods describedherein. The term “exocyclic” refers to the position of the O, N, or Swith respect to the aromatic ring system. For example, the term“exocyclic” refers to a bond in which the carbon is contained within thearomatic rings system, but the respective oxygen, nitrogen, or sulfuratoms are not and, (in the case of nitrogen), vice versa. For example,phenol, dimethylaniline, 1-methyl-1H-pyrrole, and benzenethiol containexocyclic aromatic C—O, C—N, and C—S bonds, respectively. Exemplaryorganic substrates comprise, but are not limited to, optionallysubstituted phenyl ethers, phenyl amines, phenyl sulfides, naphthylethers, naphthyl amines, or naphthyl sulfides moiety, N-alkyl or N-arylpyrroles, or combinations thereof.

Where X is O or N, the reaction favors silylation of the ring ortho orat the carbon adjacent to the carbon containing the exocyclic C—X bond.Electron-rich systems or electron-donating groups or substituents appearto be generally more reactive than electron-poor systems orelectron-withdrawing groups or substituents; the latter may require moreforcing conditions than the former, but note that more forcingconditions derived from higher temperatures may result in driving theC—X cleavage manifold—see, for example co-filed U.S. patent applicationSer. No. 14/043,917, filed Oct. 2, 2013, entitled “Transition-Metal-FreeReductive Cleavage of Aromatic C—O, C—N, and C—S Bonds by ActivatedSilanes.” Anisole and 2-methoxynaphthalene show a particular preferenceto the ortho position, and this selectivity provides the basis forembodiments comprising the selective ortho silylation of suchsubstrates. See, e.g., Examples 6.7.1 to 6.7.4.

Note that these compounds may be seen as surrogates for polymers oroligomers. For example, the demonstrated ability to silylatedimethoxybenzene, diphenyl ether, and 3-methoxynaphthalene provideenabling support for the ability to silylate polymers having linkagessuch as:

including such as polymers or copolymers of phenylene oxides,naphthalene oxides, or alkylenephenylene oxides, and methods to effectthese transformations are considered within the scope of the presentdisclosure.

Interesting, and by contrast, those substrates having an exocyclicaromatic C—X bond, where X is S-alkyl provides a different reactivity,showing a proclivity to silylate the alkyl group rather than thearomatic ring system. See, e.g., Example 6.7.5. This reactivity patternprovides a basis for those embodiments comprising the β-silylation ofsuch substrates.

In certain embodiments, the methods are applied to an organic substratecomprising a heteroaryl moiety. Non-limiting heteroaryl moieties includethose an optionally substituted furan, pyrrole, thiophene, pyrazole,imidazole, triazole, isoxazole, oxazole, thiazole, isothiazole,oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazone,benzofuran, benzopyrrole, benzothiophene, isobenzofuran,isobenzopyrrole, isobenzothiophene, indole, isoindole, indolizine,indazole, azaindole, benzisoxazole, benzoxazole, quinoline,isoquinoline, cinnoline, quinazoline, naphthyridine,2,3-dihydrobenzofuran, 2,3-dihydrobenzopyrrole,2,3-dihydrobenzothiophene, dibenzofuran, xanthene, dibenzopyrol,dibenzothiophene. In more preferred embodiments, the substrate comprisesa moiety comprising an optionally substituted furan, pyrrole, thiophene,pyrazole, imidazole, benzofuran, benzopyrrole, benzothiophene, indole,azaindole dibenzofuran, xanthene, dibenzopyrrole, or dibenzothiophenemoiety. Independent embodiments provide that the methods yield silylatedproducts substituted as described herein.

In other specific embodiments, the methods are operable on substratescomprising the following moieties:

where X is N—R″, O, or S;

Y is H, N(R″)₂, O—R″, or S—R″

p is 0 to 4, 0 to 3, 0 to 2, or 0 to 1;

R′ is a functional group “Fn,” as described above, or (R′)_(p) comprisesa fused alicyclic, heteroalicyclic (e.g., methylene, ethylene, orpropylene linked diether), aryl or heteroaryl moiety; and

R″ is an amine protecting group or an optionally substituted alkyl,aryl, heteroaryl, alkaryl or alk-heteroaryl, preferably optionallysubstituted C₁-C₆ alkyl, phenyl, tolyl, benzyl, or phenethyl.

Exemplary fused heterocyclic moieties include, for example, the groups:

Ethylenedioxothiophene is but one example of such a heteroaryl diether.

In certain more specific embodiments, the methods are operable onorganic substrates comprising the following moieties:

where X, Y, R′, R″ and p are as defined above. Note that the designation

in each case, is intended to allow for substitution on either aromaticring.

Heteroaryl moieties appear to react according to the inventive methodsunder conditions that are milder than their aryl cogeners, such that, inmixed aryl-heteroaryl systems, reactions generally proceed to silylatethe heteroaryl ring preferentially.

Also, 5-membered heteroaryl moieties appear to react according to theinventive methods under conditions that are milder than even 6-memberedheteroaryl moieties. For example, as shown in Examples 6.9.26 to 9.9.29,1H-pyrrolopyridines are shown to silylate preferentially in the5-membered heterocylic portion of the molecule. And both rings silylateunder conditions much milder than found for pyridine.

The silylation reactions with substrates comprising 5-memberedheteroaryl moieties also provide remarkably clean and apparently tunableregioselectivities. Substrates comprising 5-membered heteroaryl ringscontaining O or N apparently can silylate at the C-2 or C-3 position,depending on time and temperature, but milder conditions appear to favorsubstitution at the C-2 position. While not intending to be bound by thecorrectness or incorrectness of any particular theory, it appears thatsilylation at the C-2 position represents the kinetic result of thereaction, whereas silylation at the C-3 position is thermodynamicallyfavored. While described in terms of “kinetic” and “thermodynamic”pathways, it is not clear that silylation at a C-3 position necessarilyproceeds through a C-2 intermediate. Indeed, experiments using 1,2dimethyl indole and 2,5-dimethyl thiophene, where the C-2 positions areblocked by methyl groups, reaction proceeded to silylate thealpha-methyl group preferentially, with no evidence for silylation inthe C-3 position.

Unless otherwise stated, reference to silylation at a specific positionis intended to connote a regioselectivity or regiospecificity of aproduct at that position of greater than about 80%. But otherembodiments provide that the regiospecificity at that position isgreater than about 50%, greater than about 75%, greater than about 90%,or greater than about 95%.

The silylation reactions are also remarkably tolerant to a range offunctional groups (see, e.g., Example 7.2). Carbonyl groups in generalwere not tolerated, but can be made compatible if protected as thecorresponding acetal or ketal. Aryl-F, Aryl-Cl, Aryl-CF₃, epoxide,N-alkyl aziridine, cis- and trans-olefins, acetylene, pyridine, andtertiary amine and phosphine moieties are all compatible with thesilylation chemistry. Even free OH and NH groups are tolerated to someextent, apparently owing to a fortuitous silylative protection of theheteroatom in situ. By contrast, the presence of Aryl-Br, Aryl-I,Aryl-CN, and Aryl-NO₂ all appear to shut down the reaction. Thisversatility is important for the application of the current method to,for example, alkaloid natural product synthesis and pharmaceuticalscience applications either at an early stage or for advancedintermediate functionalization.

The products of the inventive methods are useful in a range ofagrichemical, pharmaceutical, and electronics applications, as describedinfra. Heteroarylsilane derivatives, such as described herein, are knownto undergo a variety of powerful synthetic transformations; a number ofrepresentative examples are demonstrated here (FIG. 4B). Again, each ofthese downstream transformations is accessible because of the presentinventive processes, and so these downstream steps (when coupled withthe inventive silylations) are considered within the scope of thepresent invention.

The use of aromatic silanes, such as those described herein, are usefulsynthons for the preparation of biaryl/biaromatic compounds, forexample, using the Hiyama coupling methods generally recognized in theart. As understood by the skilled artisan, the term “biaromatic” refersto two independent aromatic/heteroaromatic ring systems joined by asingle bond—e.g., bifuran, biphenyl, bipyridine, bithiophene,phenyl-pyridine, etc. The skilled artisan would be well able to combinethe teachings of these Hiyama coupling methods with those presentedhere, without undue experimentation, to prepare biaryl/biaromaticcompounds, and such preparations are considered within the scope of thepresent invention. Also, Ball and colleagues (Ball et al., Science 28Sep. 2012: Vol. 337 no. 6102 pp. 1644-1648, which is incorporated byreference herein for its teaching of the catalysts, methods, andsubstrates) have more recently described another method, using goldcatalysts, to couple trialkyl silanes, such as those described herein,to form biaryl/biaromatic compounds. Again, the skilled artisan would bewell able to combine the teachings of the Ball coupling, including atleast the second aryl compounds taught or suggested in the Ballreference, again without undue experimentation, to prepare biaryl orbiaromatic compounds, and such methods and preparations are consideredwithin the scope of the present invention. In such embodiments, asilylated product of the present invention, whether isolated orgenerated in situ, is further reacted under conditions (including thepresence of a suitable transition metal catalyst) sufficient to couplethe silylated product with a second aromatic compound to prepare thebiaryl or biaromatic product. As intended herein, the second aromaticcompound comprises an optionally substituted aromatic moiety, includingoptionally substituted aryl and heteroaryl moieties, where the terms“optionally substituted,” “aromatic,” “aryl,” and “heteroaryl” carry thesame definitions as already described herein.

Such transformations are illustrated herein. For example, C2 Si-directedSuzuki-Miyaura cross-coupling by the method of Zhao and Snieckus, orHiyama-Denmark cross-coupling via heteroarylsilanol 6, furnished2-arylated indole. An unusual direct C₇ functionalization ofbenzothiophene to give boronate esters 7 and 8 was achieved by using ablocking group strategy from silylated precursor 4h. See Examples 8.4.1and 8.4.2. This general transformation (i.e., the use of the inventivesilylation to protect/deprotect certain favorable positions) isconsidered within the scope of the present invention. Indeed, whileExamples 8.4.1 and 8.4.2 show this in the context of the C₂ position ofindoles (and by extension, benzofurans, and thiophenes), the ability toregiospecifically place and then remove a silyl group is a valuable newtool in the chemist's arsenal.

The conversion of aromatic silanes, such as those described herein, arealso known to be convertible to aromatic hydroxy compounds, using thewell-known Fleming-Tamao oxidation methods. The skilled artisan would bewell able to combine the teachings of these Fleming-Tamao oxidationswith those presented here, again without undue experimentation, toprepare hydroxylated aromatic compounds, and such methods andpreparations are considered within the scope of the present invention.In such embodiments, the aromatic silylated products of the presentinvention, whether isolated or generated in situ, are further reactedunder conditions (including the presence of a suitable transition metalcatalyst) sufficient to convert the silylated product to hydroxylatedaromatic products. Once hydroxylated, the aromatic products can beconverted to the corresponding alkyl or aryl ethers, alkyl or arylesters, halides (chloro, bromo, fluoro, iodo), nitrates, nitrites, orother similar functional groups by conventional methods. Aryl orheteroaryl iodides are especially convenient precursors for a range ofcoupling reactions (see, e.g., the palladium/copper-catalyzedsila-Sonogashira reactions of such compounds with alkynylsilanes asdescribed in Nishihara, et al., Tetrahedron Letters, 50 (2009)4643-4646). All such transformations and products resulting therefromare considered within the scope of the present invention (when conductedin conjunction with the inventive silylations)

Also, the ability of the present invention to provide silylate toprovide alpha-carbon substituents (or β-silyl groups in the case ofexocyclic sulfur) also provide that those products may be used assynthons for the Peterson olefination reaction. The known ease ofdeprotonating the alpha-methylene proton, when adjacent to the silanesilicon (the “alpha silicon effect”) to yield an alpha-silyl carbanioncan form a convenient precursor for this olefination reaction. Theskilled artisan would be well able to combine the teachings of thesePeterson olefination reaction with those presented here, again withoutundue experimentation, to replace the alpha silyl groups with alphaolefins, and such methods and preparations are considered within thescope of the present invention. In such embodiments, the aromaticsilylated products of the present invention, whether isolated orgenerated in situ, are further reacted under conditions sufficient(including the presence of a suitable transition metal catalyst) toconvert the silylated product to aromatic alpha-olefin products.

Additional embodiments include those where the aromatic silylatedproducts of the present invention, whether isolated or generated insitu, are further reacted under conditions sufficient (including thepresence of a suitable transition metal catalyst) to convert an alphasilylated product to the corresponding carboxylic acid, using themethods described, for example, in Mita, et al., Organic Letters, 2012,Vol. 14, No. 13, 3462-3465. The skilled artisan would be well able tocombine the teachings of these reactions with those presented here,again without undue experimentation, to prepare carboxylated aromaticcompounds, and such methods and preparations are considered within thescope of the present invention.

Still further embodiments include those where the aromatic silylatedproducts of the present invention, whether isolated or generated insitu, are further reacted under conditions sufficient (including thepresence of a suitable transition metal catalyst) to convert thearomatic silylated product to boronic halides and esters, halides(including chloro, bromo, and iodo), and nitroso groups using themethods described, for example, in Zhao, et al., Organic Letters, 2005,Vol. 7, No. 13, 2523-2526. The skilled artisan would be well able tocombine the teachings of these reactions with those presented here,again without undue experimentation, to prepare carboxylated aromaticcompounds, and such methods and preparations are considered within thescope of the present invention. Also, as described in the Zhaoreference, these aromatic silylated precursors, derived from the instantinvention, can also be cross-coupled with aromatic halides using theSuzuki-Miyaura cross-coupling protocols described above, to arrive atbiaromatic products.

The demonstrated ability to silylate substituted thiophenes andterthiophenes also provides for further reactions of these products withperfluoroarenes, to provide alternating thiophene-perfluoroarenecopolymers, as described in Wang Y. and Watson M., J. Amer. Chem. Soc.,2006, 128, 2536-2537. The skilled artisan would be well able to combinethe teachings of Wang and Watson with those presented here, againwithout undue experimentation, to prepare transition-metal-freealternating thiophene-perfluoroarene copolymers, and such methods andthe products derived therefrom are within the scope of the presentinvention.

Organosilicon has been extensively investigated in the development ofadvanced materials owing to silicon's unique physical and chemicalproperties. Within this context, the present disclosure providesexamples of compounds and transformations that are valuable in thematerials and pharmaceutical context (see e.g., FIG. 4C and Example8.8.1 to 8.8.5). In but one example, sila-heterocycle 9 was prepared inone step directly from the commercially available unfunctionalizedheteroarene by an unprecedented double C—H functionalization involvingintermolecular silylation followed by intramolecular silylation. Ahigh-yielding bis-silylation of thiophene oligomer 10 furnished thestarting material for an entirely transition-metal-free catalytic routeto alternating copolymers. Finally, the monoselective silylation of the3,4-ethylenedioxythiophenemonomer provided a potential strategy for themodification of polythiophene-derived materials (FIG. 4C, 11). Thegeneral ability to silylate thiophenes (including EDOT) andterthiophenes is one of the many important aspects of the presentinvention.

Sila-drug analogues have garnered much attention from medicinal chemistsbecause they can offer improved stability, solubility andpharmacokinetic properties compared with the parent all-carboncompounds. Moreover, the installed organosilicon functionality can serveas a synthetic handle for subsequent elaboration, facilitating librarysynthesis and enabling structure—activity relationship studies. As aresult, organosilicon-containing small molecules are of growing interestin pharmaceutical science, and the direct silylation of lead compoundswould thus represent a new and potentially powerful tool in drugdiscovery. To evaluate the present methods for such late-stage C—Hfunctionalization applications, the antihistamine thenalidine and theantiplatelet drug ticlopidine was subjected to representative catalyticsilylation conditions. The reactions proceeded smoothly in the case ofboth active pharmaceutical ingredients, yielding the Si-containingtarget compounds 12 and 13a-c in 56%-68% yield with excellent chemo- andregioselectivity (FIG. 4D). The piperidines, aniline, benzylic C—H bondsand aryl chloride moieties were all tolerated without any observed sidereactions. Silylation of aza analogue 14 also proceeded well,demonstrating the compatibility of these methods withpyridine-containing complex molecules of potential pharmaceuticalimportance. Finally, during these investigations, minor amounts of sp²and sp³ C—H silylation by-products at ambient temperature were observedin the cases of methoxy- and methyl-substituted indoles, respectively(that is, 15 and 16; FIG. 4E). Simple arenes react analogously. Theortho-silylation of anisole and the directing group-free C(sp³)-Hsilylation of toluene were discovered, furnishing silylated derivatives17a and 18a, respectively. Four additional examples were demonstrated,providing silylarenes (17b and 17c) and benzylsilanes (18b and 18c) withexcellent selectivity. Of particular note is the C(sp³)-H silylation of2,6-lutidine, providing an example of C—H silylation in anelectron-deficient system. Interestingly, methoxy toluene 19 and benzylether 21, both containing potentially reactive sp² and sp³ C—H bonds,were silylated with opposite selectivities to yield 20 and 22. In thecase of 22, the reaction introduces a Si-substituted chiral center.

The following listing of embodiments is intended to complement, ratherthan displace or supersede, the previous descriptions.

Embodiment 1

A chemical system for silylating an organic substrate comprising anaromatic moiety, said system comprising or consisting essentially of amixture of (a) at least one organosilane and (b) at least one strongbase, the definition of said strong base now also including hydroxide,especially KOH, said system preferably, but not necessarily, beingsubstantially free of transition-metal compounds, the strong base beingsufficient to effect the silylation of the organic moiety withouttransition metal catalyst, plasma, or UV radiation.

Embodiment 2

The system of Embodiment 1, wherein the transition-metal compound ispresent at less than 10 ppm, relative to the weight of the total system.

Embodiment 3

The chemical system of Embodiment 1 or 2, further comprising anoptionally substituted tetraalkylethylenediamine (e.g.,tetramethylethylenediamine), an optionally substituted1,7-phenanthroline derivative, an optionally substituted1,10-phenanthroline derivative, an optionally substituted2,2′-bipyridine derivatives, or an optionally substituted4-dimethylaminopyridine derivative.

Embodiment 4

The system of any one of Embodiments 1 to 3, that is substantially freeof water, oxygen, or both water and oxygen, preferably anaerobic andanhydrous.

Embodiment 5

The system of any one of Embodiments 1 to 4, wherein at least oneorganosilane comprises an organosilane of Formula (I) or Formula (II):(R)_(4-m)Si(H)_(m)  (I)R—[—SiH(R)—O—]_(n)—R  (II)where: m is 1, 2, or 3; n is 10 to 100; and each R is independentlyoptionally substituted C₁₋₁₂ alkyl or heteroalkyl, optionallysubstituted C₅₋₂₀ aryl or C₄₋₂₀ heteroaryl, optionally substituted C₆₋₃₀alkaryl or heteroalkaryl, optionally substituted C₅₋₃₀ aralkyl orheteroaralkyl, optionally substituted —O—C₁₋₁₂ alkyl or heteroalkyl,optionally substituted —O—C₅₋₂₀ aryl or —O—C₄₋₂₀ heteroaryl, optionallysubstituted —O—C₅₋₃₀ alkaryl or heteroalkaryl, or optionally substituted—O—C₅₋₃₀ aralkyl or heteroaralkyl, and, if substituted, the substituentsmay be phosphonato, phosphoryl, phosphanyl, phosphino, sulfonato, C₁-C₂₀alkylsulfanyl, C₅-C₂₀ arylsulfanyl, C₁-C₂₀ alkylsulfonyl, C₅-C₂₀arylsulfonyl, C₁-C₂₀ alkylsulfinyl, C₅-C₂₀ arylsulfinyl, sulfonamido,amino, amido, imino, nitro, nitroso, hydroxyl, C₁-C₂₀ alkoxy, C₅-C₂₀aryloxy, C₂-C₂₀ alkoxycarbonyl, C₅-C₂₀ aryloxycarbonyl, carboxyl,carboxylato, mercapto, formyl, C₁-C₂₀ thioester, cyano, cyanato,thiocyanato, isocyanate, thioisocyanate, carbamoyl, epoxy, styrenyl,silyl, silyloxy, silanyl, siloxazanyl, boronato, boryl, or halogen, or ametal-containing or metalloid-containing group, where the metalloid isSn or Ge, where the substituents may optionally provide a tether to aninsoluble or sparingly soluble support media comprising alumina, silica,or carbon.

Embodiment 6

The system of Embodiment 5, wherein the organosilane is (R)₃SiH or(R)₂SiH₂, where R is aryl, aralkyl, or C₁₋₆ alkyl.

Embodiment 7

The system of any one of Embodiments 1 to 6, wherein the at least onestrong base comprises an alkali or alkaline metal hydride or alkoxide.

Embodiment 8

The system of any one of Embodiments 1 to 7, wherein the at least onestrong base comprises an alkali or alkaline metal hydride.

Embodiment 9

The system of Embodiment 8, wherein the at least one strong basecomprises calcium hydride or potassium hydride.

Embodiment 10

The system of any one of Embodiments 1 to 7, wherein the at least onestrong base comprises an alkali or alkaline metal alkoxide.

Embodiment 11

The system of Embodiment 10, wherein the at least one alkoxide comprisesa C₁₋₁₂ linear or branched alkyl moiety or a C₅₋₁₀ aromatic orheteroaromatic moiety.

Embodiment 12

The system of Embodiment 11, wherein the at least one alkoxide comprisesmethoxide, ethoxide, propoxide, butoxide, or 2-ethyl-hexyl alkoxide.

Embodiment 13

The system of any one of Embodiments 7 to 12, wherein the alkali oralkaline metal hydride or alkoxide base is a potassium or cesiumalkoxide.

Embodiment 14

The system of any one of Embodiments 1 to 13, where the organosilane istriethylsilane and the strong base is potassium tert-butoxide.

Embodiment 15

The system of any one of Embodiments 1 to 7, wherein the at least onestrong base comprises potassium hydroxide (KOH).

Embodiment 16

The system of any one of Embodiments 1 to 15, wherein the organosilaneand the at least one strong base are present together at a molar ratio,with respect to one another, in a range of from about 20:1 to about 1:1.

Embodiment 17

The system of any one of Embodiments 1 to 15, further comprising anorganic aromatic compound, said compound being a solvent, a substrate,or both a solvent and a substrate.

Embodiment 18

The system of Embodiment 17, wherein the organic compound comprises anoptionally substituted benzene, biphenyl, naphthalene, or anthracenering structure.

Embodiment 19

The system of Embodiment 17 or 18, wherein the organic aromatic compoundcomprises a heteroaryl moiety.

Embodiment 20

The system of Embodiment 19, wherein the organic aromatic compoundcomprises an optionally substituted furan, pyrrole, thiophene, pyrazole,imidazole, triazole, isoxazole, oxazole, thiazole, isothiazole,oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazone,benzofuran, benzopyrrole, benzothiophene, isobenzofuran,isobenzopyrrole, isobenzothiophene, indole, isoindole, indolizine,indazole, azaindole, benzisoxazole, benzoxazole, quinoline,isoquinoline, cinnoline, quinazoline, naphthyridine,2,3-dihydrobenzofuran, 2,3-dihydrobenzopyrrole,2,3-dihydrobenzothiophene, dibenzofuran, xanthene, dibenzopyrol, ordibenzothiophene moiety.

Embodiment 21

The system of Embodiment 19 or 20, wherein the organic aromatic compoundcomprises an optionally substituted furan, pyrrole, thiophene, pyrazole,imidazole, benzofuran, benzopyrrole, benzothiophene, indole, azaindole,dibenzofuran, xanthene, dibenzopyrrole, dibenzothiophene, or a hindereddibenzofuran, dibenzopyrrole, or dibenzothiophene moiety.

Embodiment 22

The system of any one of Embodiments 17 to 21, wherein the organicaromatic compound comprises at least one of the following moieties:

where X is N—R″, O, or S;

Y is H, N(R″)₂, O—R″, or S—R″

p is 0 to 4, 0 to 3, 0 to 2, or 0 to 1;

R′ is a functional group “Fn,” as described above or (R′)_(p) comprisesan optionally substituted fused alicyclic, heteroalicyclic (e.g.,methylene, ethylene, or propylene linked diether), aryl or heteroarylmoiety; and

R″ is an amine protecting group or an optionally substituted alkyl,aryl, heteroaryl, alkaryl or alk-heteroaryl, preferably optionallysubstituted C₁-C₆ alkyl, phenyl, tolyl, benzyl, or phenethyl.

Embodiment 23

The system of any one of Embodiments 17 to 22, wherein the substratecomprises at least one of the following moieties:

where X, Y, R′, R″ and p are as defined above. Note that the designation

in each case, is intended to allow for substitution on either aromaticring.

Embodiment 24

The system of method of any one of Embodiments 17 to 22, wherein thearomatic organic compound comprises at least one alpha-methyl ormethylene C—H bond, said method resulting in the formation of a alphasilane.

Embodiment 25

A method of silylating a substrate comprising an aromatic moiety, saidmethod comprising contacting a quantity of the organic substrate with asystem of any one of Embodiments 1 to 24.

Embodiment 26

A method comprising contacting an organic substrate comprising anaromatic moiety with a mixture comprising or consisting essentially of(a) at least one organosilane and (b) at least one strong base, thedefinition of said strong base now also including hydroxide, especiallyKOH, under conditions sufficient to silylate the substrate; wherein saidmixture and substrate are preferably, but not necessarily, substantiallyfree of transition-metal compounds.

Embodiment 27

The method of Embodiment 26, wherein the transition-metal compound ispresent at less than 10 ppm, relative to the weight of the total system.

Embodiment 28

The method of Embodiments 26 or 27, wherein the mixture furthercomprises an optionally substituted tetraalkylethylenediamine (e.g.,tetramethylethylenediamine), an optionally substituted1,7-phenanthroline derivative, an optionally substituted1,10-phenanthroline derivative, an optionally substituted2,2′-bipyridine derivatives, or an optionally substituted4-dimethylaminopyridine derivative.

Embodiment 29

The method of any one of Embodiments 26 to 28, that is substantiallyfree of water, oxygen, or both water and oxygen.

Embodiment 30

The method of any one of Embodiments 26 to 29, wherein at least oneorganosilane comprises an organosilane of Formula (I) or Formula (II):(R)_(4-m)Si(H)_(m)  (I)R—[—SiH(R)—O—]_(n)—R  (II)where m is 1, 2, or 3 (preferably 1 or 2);

n is 10 to 100; and

and each R is independently optionally substituted C₁₋₁₂ alkyl orheteroalkyl, optionally substituted C₅₋₂₀ aryl or C₄₋₂₀ heteroaryl,optionally substituted C₆₋₃₀ alkaryl or heteroalkaryl, optionallysubstituted C₆₋₃₀ aralkyl or heteroaralkyl, optionally substituted—O—C₁₋₁₂ alkyl or heteroalkyl, optionally substituted —O—C₅₋₂₀ aryl orC₄₋₂₀ heteroaryl, optionally substituted —O—C₆₋₃₀ alkaryl or —O—C₄₋₃₀heteroalkaryl, or optionally substituted —O—C₆₋₃₀ aralkyl or —O—C₄₋₃₀heteroaralkyl, and, if substituted, the substituents may be phosphonato,phosphoryl, phosphanyl, phosphino, sulfonato, C₁-C₂₀ alkylsulfanyl,C₅-C₂₀ arylsulfanyl, C₁-C₂₀ alkylsulfonyl, C₅-C₂₀ arylsulfonyl, C₁-C₂₀alkylsulfinyl, C₅-C₂₀ arylsulfinyl, sulfonamido, amino, amido, imino,nitro, nitroso, hydroxyl, C₁-C₂₀ alkoxy, C₅-C₂₀ aryloxy, C₂-C₂₀alkoxycarbonyl, C₅-C₂₀ aryloxycarbonyl, carboxyl, carboxylato, mercapto,formyl, C₁-C₂₀ thioester, cyano, cyanato, thiocyanato, isocyanate,thioisocyanate, carbamoyl, epoxy, styrenyl, silyl, silyloxy, silanyl,siloxazanyl, boronato, boryl, or halogen, or a metal-containing ormetalloid-containing group, where the metalloid is Sn or Ge, where thesubstituents may optionally provide a tether to an insoluble orsparingly soluble support media comprising alumina, silica, or carbon.

Embodiment 31

The method of any one of Embodiments 26 to 30, wherein the organosilaneis (R)₃SiH, where R is independently C₁₋₆ alkyl.

Embodiment 32

The method of any one of Embodiments 26 to 31, wherein the at least onestrong base comprises an alkali or alkaline metal hydride or alkoxide.

Embodiment 33

The method of any one of Embodiments 26 to 32, wherein the at least onestrong base comprises an alkali or alkaline metal hydride.

Embodiment 34

The method of Embodiment 33, wherein the at least one strong basecomprises calcium hydride or potassium hydride.

Embodiment 35

The method of any one of Embodiments 26 to 34, wherein the at least onestrong base comprises an alkali or alkaline metal alkoxide.

Embodiment 36

The method of Embodiment 35, wherein the at least one alkoxide comprisesa C₁₋₁₂ linear or branched alkyl moiety or a C₅₋₁₀ aryl or C₄₋₁₀heteroaryl moiety.

Embodiment 37

The method of Embodiment 36, wherein the at least one alkoxide comprisesmethoxide, ethoxide, propoxide, butoxide, or 2-ethyl-hexyl alkoxide.

Embodiment 38

The method of any one of Embodiments 32 to 37, wherein the alkali oralkaline metal hydride or alkoxide is a potassium or cesium alkoxide.

Embodiment 39

The method of any one of Embodiments 26 to 38, where the organosilane istriethylsilane and the strong base is potassium tert-butoxide.

Embodiment 40

The method of Embodiment 26, where the organosilane is triethylsilaneand the strong base is potassium hydroxide.

Embodiment 41

The method of any one of Embodiments 26 to 29, wherein the organosilaneand the at least one strong base, the definition of strong base nowincluding hydroxide, especially KOH, are present together at a molarratio, with respect to one another, in a range of from about 20:1 toabout 1:1.

Embodiment 42

The method of any one of Embodiments 26 to 41, wherein the at least onestrong base, the definition of strong base now including hydroxide,especially KOH, and substrate are present together at a molar ratio,with respect to one another, in a range of from about 0.01:1 to about5:1, preferably in a range of from about 0.01:1 to about 0.9:1.

Embodiment 43

The method of any one of Embodiments 26 to 42, wherein the organicsubstrate comprises an optionally substituted benzene, biphenyl,naphthalene, or anthracene ring structure.

Embodiment 44

The method of any one of Embodiments 26 to 43, wherein the organicsubstrate comprises an exocyclic aromatic C—X bond, where X is N, O, orS.

Embodiment 45

The method of any one of Embodiments 26 to 44, wherein the organicsubstrate comprises an exocyclic aromatic C—X bond and the silylationoccurs ortho to the exocyclic C—X bond, where X is N, O, or S.

Embodiment 46

The method of any one of Embodiments 26 to 45, wherein the organicsubstrate comprises a heteroaryl moiety.

Embodiment 47

The method of any one of Embodiments 26 to 46, wherein the substratecomprises an optionally substituted furan, pyrrole, thiophene, pyrazole,imidazole, triazole, isoxazole, oxazole, thiazole, isothiazole,oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazone,benzofuran, benzopyrrole, benzothiophene, isobenzofuran,isobenzopyrrole, isobenzothiophene, indole, isoindole, indolizine,indazole, azaindole, benzisoxazole, benzoxazole, quinoline,isoquinoline, cinnoline, quinazoline, naphthyridine,2,3-dihydrobenzofuran, 2,3-dihydrobenzopyrrole,2,3-dihydrobenzothiophene, dibenzofuran, xanthene, dibenzopyrol, ordibenzothiophene moiety.

Embodiment 48

The method of any one of Embodiments 26 to 47, wherein the substratecomprises an optionally substituted furan, pyrrole, thiophene, pyrazole,imidazole, benzofuran, benzopyrrole, benzothiophene, indole, azaindole,dibenzofuran, xanthene, dibenzopyrrole, or a dibenzothiophene.

Embodiment 49

The method of any one of Embodiments 26 to 48, wherein the organicaromatic substrate comprises at least one of the following moieties:

where X is N—R″, O, or S;

Y is H, N(R″)₂, O—R″, or S—R″

p is 0 to 4, 0 to 3, 0 to 2, or 0 to 1;

R′ is a functional group “Fn,” as described above, or (R′)_(p) is anoptionally substituted fused alicyclic, heteroalicyclic, aryl orheteroaryl moiety; and

R″ is an amine protecting group or an optionally substituted alkyl,aryl, heteroaryl, alkaryl or alk-heteroaryl, preferably optionallysubstituted C₁-C₆ alkyl, phenyl, tolyl, benzyl, or phenethyl.

Embodiment 50

The method of any one of Embodiments 26 to 48, wherein the substratecomprises at least one of the following moieties:

where X, Y, R′, R″ and p are as defined above. Note that the designation

in each case, is intended to allow for substitution on either aromaticring.

Embodiment 51

The method of any one of Embodiments 26 to 50, wherein the organicsubstrate comprises a heteroaryl moiety of structure:

and the silylation occurs at the C-2 position of the heteroaryl ring.

Embodiment 52

The method of any one of Embodiments 26 to 51, wherein the organicsubstrate comprises a heteroaryl moiety of structure:

and the silylation occurs at the C-3 position of the heteroaryl ring.

Embodiment 53

The method of any one of Embodiments 26 to 52, wherein the aromaticsubstrate comprises at least one alpha-methyl or methylene C—H bond,said method resulting in the formation of a alpha silane.

Embodiment 54

The method of any one of Embodiments 26 to 53, wherein the aromaticsubstrate is polymeric or a polymeric precursor.

Embodiment 55

The method of any one of Embodiments 26 to 54, wherein the aromaticsilylated product is further reacted under conditions sufficient tocouple the silylated product with a second aromatic compound to preparea biaromatic product.

Embodiment 56

The method of any one of Embodiments 26 to 54, wherein the aromaticsilylated product is further reacted under conditions sufficient toconvert the silylated product to an aromatic hydroxylated (protected orfree hydroxyl), alkoxylated (or aryloxylated), or alkyl or arylcarboxylated product.

Embodiment 57

The method of any one of Embodiments 26 to 54, wherein the aromaticsilylated product is further reacted under conditions sufficient toconvert the silylated product to an aromatic alpha-olefin product.

Embodiment 58

The method of any one of Embodiments 26 to 54, wherein the aromaticsilylated product is further reacted under conditions sufficient toconvert the silylated product to an aromatic halide (chloro, bromo,fluoro, iodo), nitrate, or nitrite.

Embodiment 59

The method of any one of Embodiments 26 to 54, wherein the aromaticsilylated product is further reacted under conditions sufficient toconvert the silylated product to an aromatic alpha carboxylic acid orcarboxylic acid alkyl or aryl ester.

Embodiment 60

The method of any one of Embodiments 26 to 54, wherein the aromaticsilylated product is further reacted under conditions sufficient toconvert the silylated product to an aromatic boronic halide or boronicester.

Embodiment 61

The method of any one of Embodiments 26 to 54, wherein the silylatedthiophene product is further reacted under conditions sufficient toconvert the silylated product to an alternating thiophene-perfluoroarenecopolymer.

EXAMPLES

The following Examples are provided to illustrate some of the conceptsdescribed within this disclosure. While each Example is considered toprovide specific individual embodiments of composition, methods ofpreparation and use, none of the Examples should be considered to limitthe more general embodiments described herein.

In the following examples, efforts have been made to ensure accuracywith respect to numbers used (e.g. amounts, temperature, etc.) but someexperimental error and deviation should be accounted for. Unlessindicated otherwise, temperature is in degrees C., pressure is at ornear atmospheric.

Example 1: General Information

All reactions were carried out in dry glassware (e.g., oven- orflame-dried) under an argon atmosphere using standard Schlenk linetechniques or in a Vacuum Atmospheres Glovebox under a nitrogenatmosphere unless specified otherwise.

Solvents were dried by passage through an activated alumina column underargon. Reaction progress was monitored by thin-layer chromatography(TLC), UHPLC-LCMS or GC-FID analyses. TLC was performed using E. Mercksilica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UVfluorescence quenching, phosphomolybdic acid, or KMnO₄ staining.Silicycle SiliaFlash P60 Academic Silica gel (particle size 40-63 nm)was used for flash chromatography.

Mesitylene (puriss., ≥99.0% (GC)) was refluxed over sodium/benzophenone,then distilled. Tetrahydrofuran was purified by passage through asolvent purification column then further distilled over sodium-potassiumalloy and degassed with argon. All other solvents were purified bypassage through solvent purification columns and further degassed withargon. NMR solvents for air-sensitive experiments were dried over CaH₂and vacuum transferred or distilled into a dry Schlenk flask andsubsequently degassed with argon. Triethylsilane (99%) was purchasedfrom Sigma-Aldrich, refluxed over molecular sieves, and then distilled.It was then degassed by three freeze-pump-thaw cycles prior to use andsubsequently passed through neutral alumina. Deuterotriethylsilane (97atom % D) was purchased from Sigma-Aldrich and degassed by threefreeze-pump-thaw cycles prior to use and other commercially availableliquid reagents were treated analogously. Phenyldimethylsilane (≥98%),ethyldimethylsilane(98%) and diethylsilane (99%) were purchased fromSigma-Aldrich and distilled over CaH₂ and degassed by threefreeze-pump-thaw cycles prior to use. Other commercially availableliquid reagents were treated analogously. 1-methylindole (≥97%),benzofuran(99%), thianaphthene (98%), 1-methoxynaphthalene (≥98%),anisole (99%) and thioanisole (99%) were purchased from Sigma-Aldrichand were distilled prior to use. 2-methoxynaphthalene was recrystallizedtwice from boiling Et₂O. 1-phenylpyrrole (99%) was dissolved in Et₂O andpassed through activated alumina. The ether was removed in vacuo and thesolid residue was recrystallized twice from a 3:1 mixture of absoluteEtOH/water. 1-phenyl pyrrole (99%), diphenyl ether (≥99%),dibenzothiophene (≥99%) were purchased from Sigma-Aldrich and used asreceived. 4-methoxypyridine (97%) and 2,6-dimethoxypyridine (98%) werepurchased from Sigma-Aldrich, passed several times through neutral,activated alumina and subjected to 3 freeze-pump-thaw cycles prior touse. 1-methyl-7-azaindole was prepared following the procedure of Cheve,G. et al., Medchemcomm 2012, 3, 788. Sublimed grade KOt-Bu (99.99%) waspurchased from Sigma-Aldrich and subjected to vacuum sublimation (30mTorr, 160° C.) prior to use. Di-4-(methyl)phenyl ether, 1-naphthol,2-naphthol, 4-tert-butylanisole, 4-methylanisole, 1,3-diphenoxybenzene,2-methoxynaphthalene, and 1.0M tetrabutylammonium fluoride THF solutionwere purchased from Sigma-Aldrich and used as received.4-(Methoxy)dibenzofuran, di-4-(tert-butyl)phenyl ether, naphthyl ethers,4-(phenyl)phenyl phenyl ether, 2-ethoxynaphthalene,2-Neopentyloxynaphthalene, 2-tert-butyloxynaphthalene were synthesizedaccording to the literature procedures.

Heteroaromatic substrates were purchased from Aldrich, TCI, or Acros, orsynthesized according to literature procedures, for example (a) Kong,A.; Han, X.; Lu, X. Org. Lett. 2006, 8, 1339. (b) Islam, S.; Larrosa, I.Chem.—Eur. J. 2013, 19, 15093. (c) Huestis, M. P.; Fagnou, K. Org. Lett.2009, 11, 1357. (d) Mahadevan, I.; Rasmussen, M. Tetrahedron, 1993, 49,7337. Additionally, the following compounds were synthesized and havebeen reported previously in U.S. Pat. No. 9,000,167:4-(Triethylsilyl)dibenzofuran (3); 4,6-Bis(triethylsilyl)dibenzofuran(4); 3-(Triethylsilyl)biphenyl-2-ol (5); (3′-Triethylsilyl)biphenyl-2-ol(6); 3,3′-Bis(triethylsilyl)biphenyl-2-ol (7); o-Triethylsilyldiphenylether

Standard NMR spectroscopy experiments were conducted on a Varian Mercury(¹H, 300 MHz) spectrometer, a Varian Inova 400 MHz spectrometer, aVarian 500 MHz spectrometer equipped with an AutoX probe, or a Varian600 MHz spectrometer equipped with a Triax Probe. Chemical shifts arereported in ppm downfield from Me₄Si by using the residual solvent peakas an internal standard. Spectra were analyzed and processed usingMestReNova Ver. 7. IR spectra were obtained on a Perkin Elmer SpectrumBXII spectrometer using thin films deposited on NaCl plates and reportedin frequency of absorption (cm⁻¹). UHPLC-LCMS analyses were obtained onan Agilent 1290 ultra high performance liquid chromatography/massspectrometry equipped with an Agilent EclipsePlus C18 RRHD 1.8 μMcolumn. GC-FID analyses were obtained on an Agilent 6890N gaschromatograph equipped with a HP-5 (5%-phenyl)-methylpolysiloxanecapillary column (Agilent). GC-MS analyses were obtained on an Agilent6850 gas chromatograph equipped with a HP-5(5%-phenyl)-methylpolysiloxane capillary column (Agilent).High-resolution mass spectra (EI and FAB) were acquired by theCalifornia Institute of Technology Mass Spectrometry Facility. EPRspectra were recorded on a Bruker EMS spectrometer.

Example 2: Evaluation of Basic Activators

Throughout this specification, N-methyl indole is shown to act as anexcellent exemplar of the reactivities associated with this inventivechemistry. The effects of various bases were evaluated under thefollowing nominal conditions, with the results provided in Table 1.

TABLE 1 Effect of bases on the silylation of N-methyl indole at ambientconditions Entry^(a) R Base Solvent x t (hr) C2:C3^(b) C2 (%)^(b)  1 MeLiOt-Eu THF 100 16 — 0  2 Me NaOt-Bu THF 100 16 — 0  3 Me NaOET THF 10016 — 0  4 Me NAOAc THF 100 16 — 0  5 Me KOMw THF 100 16 — <5  6 Me KOEtTHF 100 16 — 14  7 Me KOt-Bu THF 100 16 >20:1 67  8 Me KHMDS THF 10016 >20:1 44  9 Me KOAc THF 100 16 — 0 10 Me KH THF 100 72 — 0 11 Me KOHTHF 100 16 — 0 12 Me Cs₂CO₃ THF 100 16 — 0 13 Me DABCO THF 100 16 — 0 14Me TBAF THF 100 16 — 0 15 Me CsF THF 100 16 — 0 16 Me KF THF 100 16 — 017 ^(c) Me KOt-Bu THF 20 60  4:1 98 18 ^(c) Me KOt-Bu MeOt-Bu 2060 >20:1 89 19 ^(c) Me KOt-Bu DME 20 60  3.4:1 95 20 ^(c) Me KOt-Bu Neat20 48 >20:1 88 21 ^(d) Me KHMDS THF 20 72  17:1 75 22 ^(c,e) Bn KOt-BuTHF 20 61 >20:1 90 23 ^(c,e,f) Bn KOt-Bu THF 20 96 >20:1 22 24 ^(c,e) BnKOTMS THF 20 72 >20:1 79 ^(a)Reactions performed with 0.2 mmol of 1 and0.6 mmol of Et₃SiH in 0.2 mL of solvent. ^(b)Determined by GC analysisof the crude reaction mixture using an internal standard. ^(c) At 45° C.^(d) At 35° C. ^(e) The ratio of C2:C3 and yield were determined by ¹HNMR analysis of the crude reaction mixture. ^(f) With 50 mol % of18-crown-6.

The results from Table 1 reveal that good catalysts for the C—Hsilylation reaction are categorized by the combination of a bulky basicanion and a potassium cation: KOt-Bu proved to be ideal catalyst andoperated under neat conditions or in THF and MeOt-Bu (Entry 18, 20 and22), but KHMDS (Entry 21) and KOTMS (Entry 24) were also effective. Thecomplete lack of reactivity with LiOt-Bu and NaOt-Bu (Entries 1 and 2)as well as the precipitous drop in reactivity when 18-crown-6 is addedto KOt-Bu (Entry 23) lend support to the crucial, albeit unknown, roleof the potassium cation. Conversion roughly correlates with basicity instoichiometric reactions (i.e., Ot-Bu>OEt>OMe; Entries 5-7). No productwas observed in the absence of catalyst, or when KH, KOH, KOAc andCs₂CO₃ were employed (Entries 9-12), under these conditions. Note thatthe previous finding that KOH was unreactive in these reactions has nowbeen confirmed, but by altering the reaction conditions, it is nowpossible to realize these transformations with this catalyst (seeExample 9 for KOH). The organic base DABCO and common fluoride-basedactivators for silicon—TBAF, CsF, and KF—were also investigated andfailed to convert the starting material (Entries 13-16). Headspace GCTCDanalysis of successful silylation reactions indicated the formation ofH₂

Interestingly, other potential chelants did not inhibit, and in manycases, improved both yield and selectivity of the systems. This effectis not well understood. Without being bound by the correctness of thisor any other theory, it is possible that these ligands chelated thepotassium cation is proposed. Bipyridine-based ligand scaffolds as wellas TMEDA (not shown) were demonstrated to be most effective in promotinghigh selectivity and efficiency in the silylation reaction. This issupported by the reaction with 1,7-phenanthroline, which is unable tochelate potassium, giving a lower product yield.

TABLE 2 Effect of bases on the silylation of N-methyl indole at ambientconditions Ligand Yield C2 Selectivity 1,10-phenanthroline 20.7 >95%1,7-phenanthroline 11.4 >95% bathophenanthroline 33.7 >95% bipyridine64.8 >95% 4,4′-di-t-Bu bipyridine 60 >95% Yields and selectivitiescalculated using GC-FID analysis with mesitylene added as a standard forquantification. C2 selectivity defined as yield (C2 product/yield C2 +C3 products) × 100%.

The activity of the inventive systems and methods were remarkablytolerant of different base loadings. In the N-methylindole model system,for example, decreasing base loading only mildly decreased efficiency.Remarkably, KOtBu even down to 1 mol % was effective and gave the majorC2 product in 65% yield and a corresponding 89% C2 selectivity. Thisloading is even lower or equal to that required for the state-of-the-arttransition-metal-based aromatic C—H silylation systems.

Example 3: Control Experiments and Trace Metal Analyses Example 3.1:Control Reactions with Commercially Available KOt-Bu, Re-SublimedKOt-Bu, and Freshly-Prepared KOt-Bu

Three reactions were performed in parallel (THF, 45° C., 1-methylindole,20 mol % KOt-Bu, 0.2 mmol scale): a) KOt-Bu (Aldrich, sublimed grade,99.99%, trace metal basis) was used as received; b) KOt-Bu (Aldrich,sublimed grade, 99.99% trace metal basis) was used after re-sublimationby heating the material under vacuum; and c) KOt-Bu, freshly prepared byreaction of potassium metal with anhydrous t-BuOH followed byevaporation of the t-BuOH and sublimation of the solid, was used. Noappreciable differences in conversion and selectivity in these reactionswere observed.

Example 3.2: Control Reaction with KOt-Bu of Different Grade Purchasedfrom Different Vendors

Four reactions were performed in parallel (THF, 45° C., 1-benzylindole,20 mol % KOt-Bu, 0.2 mmol scale): a) KOt-Bu (Aldrich, sublimed grade,99.99% trace metal basis), b) KOt-Bu (Strem, 98%), c) KOt-Bu(TCI, >97%), and d) KOt-Bu (Alfa-Aesar, 97%). The reactions weremonitored by UHPLC-LCMS. The conversion to product was greater than 90%complete after 90 hrs, and no appreciable differences in conversion andselectivity in these four reactions was observed.

Example 3.3

500 mg samples each of KOt-Bu from the four different vendors (Strem,Aldrich, TCI, Alfa-Aesar), 1-benzylindole, Et₃SiH, THF, and a standardreaction mixture (0.5 mmol scale mixture, prepared following the generalprocedure with 103.5 mg of 1-Bn-indole, 11.2 mg of KOt-Bu from Aldrich,173.5 mg of Et₃SiH in 0.5 mL of THF and stirred in the glovebox for 72h.) were analyzed. Each sample was added to a 50 mL DigiTUBE digestiontube (SCP Science) followed by addition of 3.0 mL of Plasma Pure nitricacid (SCP Science) and heating to 75° C. for 36 hours. After digestion,each sample was diluted using Milli Q water to 50 mL and sample analysiswas performed on an Agilent 7900 ICP-MS spectrometer. LOD indicates thatthe analyte concentration is below the instrument's Lowest Limit ofDetection. Values in ppb (microgram per liter).

TABLE 3 ICPMS Trace Metal Analysis - Agilent 7900 (quantities in ppb)KOt-Bu KOt-Bu KOt-Bu KOt-Bu Strem TCI Alpha Aldrich 1-Bn- Rxn Element(98%) (>97%) (97%) (99.99%) THF HSiEt₃ indole Mixture Ti 0.360 0.0510.138 0.464 LOD 2.073 9.408 31.082  Mn 1.343 1.168 1.338 1.525 LOD 0.17788.191  LOD Fe 12.285  10.171  13.080  14.036  1.691 9.531 86.191  LODCo 0.005 LOD 0.006 0.008 0.001 0.006 0.416 LOD Ni 0.064 LOD 0.232 1.4180.011 LOD 16.540  19.826  Cu 0.134 0.211 1.126 0.366 LOD 0.520 17.936 3.092 Zr 0.038 LOD LOD 0.633 LOD 0.031 LOD 8.889 Mo 2.005 1.650 1.7442.243 LOD LOD LOD LOD Ru 0.002 0.002 0.001 0.008 LOD 0.004 0.146 LOD RhLOD LOD LOD 0.001 LOD LOD LOD LOD Pd 0.014 0.006 0.029 0.116 0.002 0.0040.070 0.593 Ag 0.001 LOD 0.290 0.015 LOD 0.004 0.055 0.013 Os 0.001 LODLOD 0.001 LOD LOD 0.007 0.016 Ir 0.001 0.001 0.002 0.026 LOD 0.001 0.0470.041 Pt 0.009 0.004 0.002 0.010 LOD 0.001 LOD LOD Au 0.017 0.013 0.0130.023 0.108 0.024 0.738 1.582

Example 4: Investigation into the Radical Nature of the KOt-Bu-CatalyzedC—H Silylation

A number of experiments were conducted to gain insight into the reactionmechanism. As a first investigation, the reaction was performed in thepresence of the radical traps TEMPO and galvinoxyl. Under conditionsotherwise conducive to silylation of N-methyl indole both additivesthwarted the C—H silylation.

In a second set of experiments, three control experiments in an attemptto probe the role of TEMPO. A trace amount of triethylsilyl protectedproduct II was observed at 23° C. with 1 equivalent of TEMPO, presumablyarising from the radical combination of a silyl radical and TEMPOitself. Product II became the major component of the mixture when thetemperature was raised to 65° C., lending support to the involvement ofsilyl radical species in the silylation reaction. In contrast, thisprotected compound II is not observed in the absence of KOt-Bu,indicating that the catalyst is critical to generate the silyl radical.

To evaluate the possible contribution of a polar mechanism (i.e.,formation of silyl anions), experiments were conducted on theKOt-Bu-catalyzed reaction with benzothiophene 3h as a substrate in thepresence of cyclohexene oxide as an additive (epoxides, includingcyclohexene oxide, are known to undergo nucleophilic ring opening bysilyl anions). However, under standard ambient conditions used in thetest, the epoxide was quantitatively recovered after the reaction, andthe desired silylation product 4h was obtained in moderate yield,providing evidence against the formation of discrete silyl anions.

Example 5: General Procedure

In a nitrogen-filled glovebox, a 2 dram scintillation vial or 4 mL screwcap vial was loaded with the corresponding substrate (0.1-0.5 mmol, 1equiv.), base (e.g., KOt-Bu or KOH, 0.1-5 equiv.) and a magneticstirring bar, followed by syringe addition of the solvent (1 mL) andsilane (1-5 equiv. filtered through a short pad of activated aluminabefore use). The reaction vial was sealed with and the mixture wasstirred at the indicated temperature for the indicated time. The vialwas removed from the glove box, the reaction mixture was diluted withdiethyl ether (2 mL) and concentrated under reduced pressure. Theregioselectivity (C2 silylation product to C3 silylation product: C2:C3)was determined by ¹H NMR or GC analysis of the crude mixture. Theresidue was purified by silica gel flash chromatography to give thedesired product.

Unless stated otherwise, in preparative experiments only products withthe overall yield exceeding 2% were isolated and characterized. In thecase of naphthyl alkyl ethers, a different workup procedure was used.After cooling, the reaction was diluted with dichloromethane (5 mL) andcarefully quenched with 2 mL of 1 N aqueous HCl. Tridecane was added,and the mixture was transferred to a separatory funnel. The organicphase was separated, and the aqueous layer was extracted withdichloromethane (3 mL). The combined organic layers were dried overanhydrous MgSO₄ and filtered. For all reactions, the products wereidentified using GC/MS and GC/FID and NMR by comparison with theauthentic samples. Trace soluble side products observed in naphthylalkyl ether reductions included naphthalene,1,2,3,4-tetrahydronaphthalene, and 5,6,7,8-tetrahydro-2-naphthol.

In most cases, the products were isolated and purified beforecharacterization by NMR and/or GC-MS, either by independent spectralanalysis or comparison with authentic samples, or both. In those caseswhere the product was not isolated and purified, characterization wasmade on the basis of GC-MS and/or GC-FID analyses.

Example 6: Selected Reactions Example 6.1: Reactions of4-(Triethylsilyl)dibenzofuran

The reaction was conducted according to the General Procedure by heating4-Et₃Si-dibenzofuran (3, 141 mg, 0.5 mmol, 1 equiv.), KOt-Bu (112 mg, 1mmol, 2 equiv.) and Et₃SiH (401 microliters, 2.5 mmol, 5 equiv.) in 2 mlof toluene for 20 hours at 100° C. After acidic aqueous work up, thecrude reaction mixture was purified by chromatography on silica usinghexanes and hexanes-ether (10:1) to isolate 2-phenylphenol (2, 30 mg,0.177 mmol, 35%), 2-triethylsilyl-6-phenylphenol (5, 37 mg, 0.134 mmol,26%), 2-(3-triethylsilylphenyl)phenol (6, 17 mg, 0.063 mmol, 12%).Quantities of unconsumed 3 as well as products 1, 4 and 7 were obtainedusing post-chromatography GC-FID analysis of the corresponding mixedfractions.

Example 6.2: Investigation of Silylated Dibenzofurans as IntermediatesTowards C—O Bond Cleavage: Cleavage Attempts with KOt-Bu

Starting material 3 (14.1 mg, 0.05 mmol, 1 equiv.) was heated withKOt-Bu (5.6 mg or 11.2 mg, 1 or 2 equiv., respectively) in 0.8 mld-toluene at 100° C. for 20 hours in a J. Young tube under nitrogen.Monitoring the reaction progress by ¹H NMR showed no conversion of 3 inboth cases. Likewise, starting materials 3 (28.2 mg, 0.1 mmol, 1 equiv.)or 4 (39.6 mg 0.1 mmol, 1 equiv.) were heated with KOt-Bu (36.6 mg) in0.3 mL of mesitylene at 160° C. for 20 hours. Subsequent analysis of thecrude reaction mixtures by GC-FID or 1H NMR revealed 3% conversion to 1in case of 3 and 5% conversion to 3 from 4.

Example 6.3: Reactions of 4-(Methoxy)dibenzofuran at ElevatedTemperature

The reaction was conducted according to the General Procedure by heating4-MeO-dibenzofuran (8, 89 mg, 0.5 mmol, 1 equiv.), KOt-Bu (112 mg, 1mmol, 2 equiv.) and Et₃SiH (401 microliters, 2.5 mmol, 5 equiv.) in 2 mlof toluene for 20 hours at 100° C. After aqueous work up, the crudereaction mixture was purified by chromatography on silica using hexanesand hexanes-ether to recover unconsumed starting material 8 (3 mg, 0.015mmol, 3%) and isolate dibenzofuran (1, 8.4 mg, 0.05 mmol, 10%; sincefractions of 1 contained small amounts of starting 8, quantification wasdone by ¹H-NMR with CH₂Br₂ as an internal standard), 1,1′-biphenyl-2-ol(2, 4.3 mg, 0.025 mmol, 5%), 4-Et₃Si-dibenzofuran (3, 11 mg, 0.039 mmol,8%), 2-methoxy-6-phenyl-phenol (9, mg, 0.025 mmol, 5%),2-(3′-methoxyphenyl)phenol (10, 47 mg, 0.235 mmol, 47%). Note: onlycompounds with the yield exceeding 2% were characterized. ¹H and ¹³C NMRspectral assignments of 9 and 10 were consistent with literaturereports.

Example 6.4: Triethylsilylation of Arenes Example 6.4.1: At ElevatedTemperatures

In many instances the formation of the solvent-derived silylatedproducts was observed at elevated temperatures during experiments aimedat C—O, C—N, or C—S bond cleavage when using toluene or mesitylene assolvents at the elevated temperatures used in the reductive cleavagereactions. Since it was not possible to separate the resulting productsfrom their respective parent solvents by column chromatography ordistillation, at this point it was difficult to assess their yields, butthey are tentatively estimated to be in 5-10% range based on Et₃SiH. Incase of toluene, the identity of products was confirmed by comparison ofthe NMR spectra obtained with the literature data (Rychnovsky, et al. J.Org. Chem. 2003, 68, 10135.) Thus, it was concluded that the majorproduct is benzyl triethylsilane (17), which is also consistent with theGC-MS analysis of fragmentation patterns of isomeric products. Likewise,it appeared that silylation of mesitylene proceeds predominantly intothe benzylic (or alpha) position. HRMS [C₁₅H₂₆Si] calculated 234.1804,measured 234.1804).

Example 6.4.2: Direct C(sp³)-H Silylation Reactions

Benzyltriethylsilane 18a:

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), toluene (46 mg, 0.5 mmol, 1equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv) and DME (0.5 mL) at 65° C.for 108 h. C(sp³):C(sp²)=18:1. The GC yield of desired product 18a is53%. The analytically pure product (25.0 mg, 24% yield) was obtained asa colorless oil after evaporation of starting material and volatilesunder vacuum (60 millitorr, 23° C.). Note: compound 18a is volatile andreadily removed under vacuum. Rf=0.8 (100% hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.22 (m, 2H), 7.09-7.05 (m, 1H), 7.05-7.02 (m, 2H), 2.12 (s,2H), 0.96-0.91 (t, 9H), 0.53 (q, J=7.9 Hz, 6H).

Triethyl((4′-methyl-[1,1′-biphenyl]-4-yl)methyl)silane 18b

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 23 mol %), 4,4′-dimethyl-1,1′-biphenyl (80.0mg, 0.44 mmol), Et₃SiH (240 μL, 1.5 mmol, 3.4 equiv), and 0.5 mL of THFat 85° C. for 96 h. The ratio of mono-silylation product tobis-silylation product is 16:1. A mixture of desired product 18b andstarting material 4,4′-dimethyl-1,1′-biphenyl (69.7 mg of mixture,contains 56.6 mg of 18b, 43% yield, calculated based on 1H NMR) wasobtained after purification by silica gel flash chromatography (100%hexanes). A small fraction of analytically pure compound 18b wasobtained as a colorless oil after subsequent purification by silica gelflash chromatography. Rf=0.5 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.50-7.47 (m, 2H), 7.46-7.42 (m, 2H), 7.25-7.21 (m, 2H), 7.11-7.04 (m,2H), 2.39 (s, 3H), 2.14 (s, 2H), 0.95 (t, J=7.9 Hz, 9H), 0.54 (q, J=8.0Hz, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 139.7, 138.5, 136.7, 136.5, 129.6,128.6, 126.8, 126.7, 21.4, 21.2, 7.5, 3.1; IR (Neat Film, NaCl) 3022,2951, 2909, 2873, 1610, 1497, 1455, 1416, 1238, 1209, 1153, 1005, 845,806, 773, 729 cm⁻¹; HRMS (EI+) calc'd for C₂₀H₂₈Si [M+.]: 296.1960,found 296.1954.

2-Methyl-6-((triethylsilyl)methyl)pyridine 18c

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 2,6-lutidine (53.5 mg, 0.5 mmol),Et₃SiH (240 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 65° C. for 120h. The desired product 18c (58.6 mg, 53% yield) was obtained afterpurification by silica gel flash chromatography (gradient elution,5%→10% EtOAc in hexanes) as a colorless oil. Note: compound 18c isvolatile and is readily removed under vacuum. Rf=0.3 (5% EtOAc inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.36 (t, J=7.6 Hz, 1H), 6.90-6.73(m, 2H), 2.47 (s, 3H), 2.32 (s, 2H), 0.98-0.83 (m, 9H), 0.58-0.48 (m,6H); ¹³C NMR (126 MHz, CDCl₃) δ 160.8, 157.4, 135.9, 119.0, 118.4, 25.4,24.5, 7.2, 3.3; IR (Neat Film, NaCl) 3060, 2951, 2874, 1587, 1575, 1450,1414, 1372, 1269, 1238, 1145, 1078, 1016, 919, 796, 748, 726 cm⁻¹; HRMS(EI+) calc'd for C₁₃H₂₄NSi [M+H]+: 222.1678, found 222.1666.

Silylation of 2,5-dimethyl thiophene

The reaction was conducted according to the General Procedure by heating2,5,dimethyl thiophene (56 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11.2 mg, 0.1mmol, 0.2 equiv.) and Et₃SiH (3 equiv.) in tetrahydrofuran for 45 hoursat 65° C. GC-MS of the crude product mixture yielded a mass peakassociated with the monosilated derivative. ¹H NMR data were consistentwith formation of 2-methyl-5-(triethylsilylmethyl)thiophene. ¹H NMR (500MHz, THF-d8) δ 6.52-6.42 (m, 1H), 6.41-6.29 (m, 1H), 2.35 (s, 3H), 2.23(s, 2H), 1.00-0.92 (m, 9H), 0.63-0.53 (m, 6H). ¹³C NMR (126 MHz, THF-d8)δ 140.78, 136.28, 125.96, 124.03, 15.73, 15.45, 7.97, 4.08. HRMS:[C₁₂H₂₂SSi] calculated 226.1212, measured 226.1220

Silylation of N-methyl-2-methylindole

The reaction was conducted according to the General Procedure by heating1,2-dimethylindole (73 mg, 0.5 mmol, 1 equiv.), KOt-Bu (17 mg, 0.15mmol, 0.3 equiv) and Et₃SiH (319 microliters, 2.0 mmol, 4 equiv.) in 1mL of tetrahydrofuran for 65 hours at 65° C. After aqueous work up, thecrude reaction mixture was purified by chromatography on silica using an80:1:4 mixture of hexanes:Et₂O:Et₃N respectively to obtain 74 mg (57%)of the title compound as a colourless oil. ¹H NMR (500 MHz, THF-d₈) δ7.35-7.29 (m, 1H), 7.19 (dd, J=8.1, 0.9 Hz, 1H), 6.97 (ddd, J=8.2, 7.1,1.2 Hz, 1H), 6.90 (ddd, J=8.0, 7.1, 1.1 Hz, 1H), 6.06 (d, J=0.8 Hz, 1H),3.64 (s, 3H), 2.25 (d, J=0.7 Hz, 2H), 0.96 (t, J=7.9 Hz, 9H), 0.71-0.58(m, 6H). ¹³C NMR (126 MHz, THF-d₈) δ 139.50, 138.30, 129.69, 120.24,119.70, 119.47, 109.27, 98.96, 29.75, 11.73, 7.62, 4.16. HRMS:[C₁₆H₂₅NSi] calculated 259.1756, measured 259.1754. The HSQC spectrum ofthis reaction product has previously been reported in U.S. Pat. No.9,000,167.

Triethyl(phenoxy(phenyl)methyl)silane 22

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), (benzyloxy)benzene 21 (92.0 mg,0.5 mmol), Et₃SiH (240 μL, 1.5 mmol, 3 equiv), and 0.25 mL of THF at 65°C. for 120 h. The desired product 22 (68.4 mg, 46% yield) was obtainedafter purification by silica gel flash chromatography (100% hexanes) asa colorless oil. Rf=0.3 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.46-7.37 (m, 4H), 7.38-7.28 (m, 4H), 7.30-7.20 (m, 2H), 5.80 (s, 1H),0.92 (t, J=7.9 Hz, 9H), 0.66-0.55 (m, 6H); ¹³C NMR (126 MHz, CDCl₃) δ145.3, 128.1, 128.1, 126.9, 126.9, 126.4, 126.3, 6.7, 4.9; IR (NeatFilm, NaCl) 3063, 3026, 2954, 2875, 1598, 1492, 1454, 1413, 1302, 1239,1188, 1090, 1065, 1006, 974, 833, 740, 700 cm⁻¹; HRMS (EI+) calc'd forC₁₉H₂₅OSi [(M+H)−H2]+: 297.1675, found 297.1668.

Aromatic amines are also amenable to silylation. In the following case,GC-MS identified the following scheme was operable under the conditionsprovided:

At lower temperatures, this reaction appeared to provide a mixture ofproduct, with no single product identifiable. It is possible, though notconfirmed, that the apparent normal proclivity to silylate ortho to theexocyclic amine was inhibited by the steric bulk associated with the twomethyl groups.

Example 6.5: Silylation of Dibenzofuran at Elevated Temperatures

Experiments were conducted using the General Procedures, unlessotherwise indicated. Yields were reproducible within ±2%. It isnoteworthy here that low levels of base, especially substoichiometricamounts of base relative to the substrate, even at these elevatedtemperatures, resulted in the highest yields of silylated products,relative to cleavage products.

TABLE 4 Results of silylation of dibenzofuran at elevated temperatures

Et₃SiH Base Conv Entry (equiv) (equiv) Solvent T, ° C. (%) ^(a) 2 3 4 56 7 1 0 KOt-Bu Toluene 100 0 — — — — — — (2) 2 5 None Toluene 100 0 — —— — — —  3^(a) 5 KOt-Bu Toluene 100 70 34 28 4 — — — (2)  4^(b) 5 KOt-BuToluene 100 98 38 16 10 21 2 7 (2)  5^(c) 5 KOt-Bu Toluene 100 98 5 2846 — — — (2) 6 4 KOt-Bu Toluene 100 100 41 17 15 12 1 9 (2) 7 3 KOt-BuToluene 100 96 42 20 9 13 1 4 (2) 8 2 KOt-Bu Toluene 100 87 34 30 10 6 13 (2) 9 1 KOt-Bu Toluene 100 56 19 29 1 2 — 1 (2) 10 5 KOt-Bu Toluene100 89 12 48 20 9 — 1 (0.5) 11 2 KOt-Bu Toluene 100 66 9 43 8 2 — — (5)12 3 KOt-Bu Toluene 100 97 63 10 1 22 — 2 (2) 13 5 KH (1) Dioxane 100 491 43 5 — — — 14 5 KOt-Bu Dioxane 100 70 25 28 10 4 1 1 (2)  15^(d) —KOt-Bu Et₃SiH 100 99 26 13 25 11 1 21 (2) 16 5 KOt-Bu Toluene 80 98 2918 26 9 — 7 (2) 17 3 KOt-Bu Mesitylene 165 100 85 3 — 5 2 — (3)  18^(e)3 KOt-Bu Mesitylene 165 100 95 — — — — — (3) 19 2 KOt-Bu Mesitylene 165100 62 8 1 12 1 — (2) 20 3 KOt-Bu Mesitylene 165 97 52 17 5 16 1 2 (2)21 1 KOt-Bu Mesitylene 165 57 30 21 — — — — (1) 22 3 KOt-Bu Mesitylene165 85 29 35 15 4 — 2 (0.5) 23 5 KOt-Bu Mesitylene 165 100 77 3 0 3 8 —(5) 24 3 KH (3) Mesitylene 165 100 66 3 0 5 11 — 25 3 KOEt Mesitylene165 100 85 4 0 1 8 — (3) 26 3 KOEt Mesitylene 165 95 77 10 11 — — — (3)27 3 KOEt Toluene 100 40 19 19 2 — — — (3) 28 3 KOMe Mesitylene 165 6431 27 2 3 1 — (3) 29 3 NaOt- Mesitylene 165 0 — — — — — — Bu (3) 30 3LiOt-Bu Mesitylene 165 0 — — — — — — (3) 31 3 NaOEt Mesitylene 165 0 — —— — — — (3)  32^(f) 3 CsOR Toluene 100 89 75 3 11 — — — (2) 33 3 KOt-BuBenzene 85 96 37 20 13 12 — 9 (3) 34 5 KOt-Bu DMF 100 0 — — — — — — (2)35 5 KOt-Bu DMA 100 0 — — — — — — (2) 36 5 KOt-Bu Diglyme 100 0 — — — —— — (2) 37 5 KOt-Bu t-BuOH 100 0 — — — — — — (2) 38 5 KOt-Bu Diisopropyl100 0 — — — — — — (2) carbonol 39 3 KOt-Bu Methyl 160 100 82 — — 13 (3)cyclohexane  40^(g) PMHS KOt-Bu Methyl 85 5-7 — — — — — — (10) (3)cyclohexane ^(a)GC yields and conversions are reported using tridecaneas the standard ^(b)the reaction was performed in 0.05M solution.^(c)reaction conducted open to an Ar line ^(d)the reaction was performedin neat Et₃SiH. ^(e)with 1,4-cyclohexadiene (100 equivalent) co-solvent^(f)R = 2-ethylhexyl. ^(g)using polymethylhydrosiloxane (PMHS) insteadof Et₃SiH as organosilane

Example 6.6: Silylation of Aryl Alkyl Ethers at Elevated Temperatures

Silylations of aryl alkyl ethers at elevated temperatures were conductedunder the conditions applied to diaryl ethers to probe the cleavageselectivity of sp² versus spa C—O bond. At the elevated temperatures ofthese experiments, the reaction of 2-methoxynaphthalene gave 2-naphtholas the major product in moderate yield (Scheme 1). GC-MS analysis of thecrude reaction mixture indicated the presence of trace amounts ofnaphthalene along with 2-methylnaphthalene and further reduced species,including products of partial aromatic reduction. Compounds presumablyderived from 2-naphthol silylation were also detected. Likewise,cleavage of 2-ethoxynapthalene under the same conditions gave 2-naphtholin slightly higher yield, but with the same or analogous side products.Sterically bulkier ethers were investigated to probe the versatility andpossible mechanism of the C—O bond cleavage. Despite the large alkylsubstituent adjacent to the ether oxygen, reaction of2-neopentyloxynaphthalene provided 2-naphthol in approximately the sameyield as with the less bulky substrates. Even 2-tert-butyloxynapthalenewas cleaved to give the expected naphthol in 55% yield (Scheme 1).Control experiments performed at identical conditions but withouttriethylsilane provided 2-naphthol in cases of 2-ethoxy- and2-tert-butyloxynapthalene albeit with substantially diminished yields.Since 2-methoxy- and 2-neopentyloxy-substrates remained intact in suchsilane-free cleavages, a b elimination mechanism is likely to beoperative. When attempting to reduce 4-tert-butyl and 4-methyl anisolesunder the standard conditions, the yields of the corresponding phenolswere high, likely because of more challenging silylation of thesubstituted phenyl ring for the steric reasons (Scheme 2).

Overall, the selectivity for alkyl C—O bond scission contrasts with thatobserved in Ni- and borane catalyzed C—O cleavage reactions where arylC—O reduction occurs. It is also notable that under these conditionsonly trace amounts of naphthalene ring hydrogenation products wereobserved, which contrasts with the results of silane-based ionichydrogenations reported in the literature.

It was instructive to compare the cleavages of methoxysubstituted diarylethers 8 and 11 (Scheme 2) with the results presented above. While arylalkyl ethers show strong preference for the reduction of alkyl oxygenover aryl oxygen bonds, both methoxy substrates in Scheme 2 demonstratea reversal of regioselectivity, furnishing almost exclusively aryloxygen bond rupture products. While not intending to be bound by thecorrectness of this theory, this effect may be attributed to thepresence of a donor oxygen atom ortho to the C—O bond undergoingrupture. Supporting this inference is the high selectivity of thereductive ring-opening of dibenzofuran derivative 8 that mainly leads to10. Likewise, preferred formation of phenol and anisole is observed withsimilar selectivity over phenols 12 and 13 in the cleavage of ligninmodel 11. One may speculate that such an effect can be rationalized bythe oxygen atom resonance stabilization of the positive charge build upduring electrophilic activation of the C—O bond that is being broken. Inorder to test this hypothesis, compound 3 was subject to the reactionconditions and isolated the ring opened phenols 5 and 6 along with thedesilylated products 1 and 2 (Scheme 2, inset C). In the absence ofresonance stabilization, the selectivity of cleavage was reversed infavour of isomer 5. It is also worth noting that, as formation of 1 and2 demonstrates, the silylation reaction is thus reversible under thetypical reaction conditions. After having illustrated the potential forthe challenging 4-O-5 lignin models 8 and 11, this method was testedwith an oligomeric ether 14 that contains six C_(ar)—O bonds (Scheme 2,inset D). Remarkably, at 165° C. in mesitylene quantitative conversionof 14 was achieved and gave phenol, benzene, resorcinol and otherunidentified products with merely 0.5 equivalent of silane per aryloxygen bond.

In Scheme 2, compounds 1 to 7 refer to the corresponding compoundsdescribed in Example 6.5.

Example 6.7: Silylation of Aryl Alkyl Ethers and Thioethers at Ambientor Near Ambient Temperatures Example 6.7.1:Triethyl(2-methoxyphenyl)silane

The reaction was conducted according to the General Procedure by heatinganisole (54 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv)and Et₃SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL oftetrahydrofuran for 65 hours at 65° C. After aqueous work up, the crudereaction mixture was purified by chromatography on silica using hexanes(isochratic) to obtain 59 mg (54%) of the title compound as a colourlessoil. ¹H NMR (500 MHz, THF-d8) δ 7.40-7.17 (m, 2H), 7.01-6.81 (m, 2H),3.77 (s, 3H), 1.02-0.85 (m, 9H), 0.87-0.74 (m, 6H). ¹³C NMR (126 MHz,THF-d8) δ 164.58, 135.52, 130.42, 123.92, 120.08, 109.23, 54.09, 6.93,3.22.

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), anisole (54.0 mg, 0.5 mmol, 1equiv), and Et₃SiH (243 μL, 1.5 mmol, 3 equiv) without any added solventat 85° C. for 72 h. ortho:(meta+para)>20:1. The GC yield of desiredproduct 17a is 65%. The analytically pure product (47.7 mg, 43% yield)was obtained as a colorless oil after evaporation of starting materialand volatiles under vacuum (60 millitorr, 23° C.). Note: compound 17a isvolatile and can be removed under vacuum. Rf=0.3 (10% Et2O in hexanes).1H NMR (500 MHz, CDCl₃) δ 7.41-7.30 (m, 2H), 6.97 (m, 1H), 6.87-6.81 (m,1H), 3.80 (s, 3H), 1.05-0.90 (m, 9H), 0.91-0.77 (m, 6H).

Example 6.7.2: Triethyl(3-methoxynaphthalen-2-yl)silane

The reaction was conducted according to the General Procedure by heating2-methoxynaphthalene (79 mg, 0.5 mmol, 1 equiv.), KOt-Bu (19.6 mg, 0.18mmol, 0.35 equiv.) and Et₃SiH (319 microliters, 2.0 mmol, 4 equiv.) in 1mL of tetrahydrofuran for 48 hours at 65° C. After aqueous work up, thecrude reaction mixture was purified by chromatography on silica elutingwith hexanes (isochratic) to obtain 79 mg (58%) of the title compound ascolourless oil. ¹H NMR (500 MHz, THF-d8) δ 7.84 (s, 1H), 7.78-7.73 (d,1H), 7.73-7.68 (d, 1H), 7.38 (ddd, J=8.2, 6.8, 1.3 Hz, 1H), 7.27 (ddd,J=8.1, 6.8, 1.2 Hz, 1H), 7.15 (s, 1H), 3.90 (s, 3H), 1.01-0.90 (m, 9H),0.68-0.53 (m, 6H). ¹³C NMR (126 MHz, THF-d8) δ 163.03, 137.88, 136.83,130.10, 128.58, 128.09, 127.29, 127.21, 124.03, 104.57, 55.25, 8.02,7.48.

HRMS: [C₁₇H₂₄OSi] calculated 272.1608, measured 272.1596. The HSQCspectra of the 2-methoxynaphthalene and its reaction product haspreviously been reported in U.S. Pat. No. 9,000,167.

Interestingly, the reaction starting with 1-methoxynaphthalene did notresult in silylated product:

The reaction was conducted according to the General Procedure by heating1-methoxynaphthalene (79 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11.2 mg, 0.1mmol, 0.1 equiv) and Et₃SiH (240 microliters, 1.5 mmol, 3 equiv.) in 1mL of tetrahydrofuran for 65 hours at 65° C. The reaction was dilutedwith diethyl ether (1 mL), quenched with water (0.5 mL) and the organicphase was analyzed by GC-MS, GC-FID and 1H NMR analysis. Analysis byGC-MS and GC-FID (tridecane standard) revealed the formation of aryl C—Ocleavage product naphthalene and alkyl C—O bond cleavage productnaphthol in 13 and 8 percent yield respectively, notably to the completeexclusion of any silylated species.

Example 6.7.3: Silylation of Diphenyl Ether

The reaction was conducted according to the General Procedure by heatingphenyl ether (85 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.10 mmol, 0.2equiv) and Et₂SiH₂ (194 microliters, 1.5 mmol, 3 equiv.) in 1 mL oftetrahydrofuran for 65 hours at 65° C. After aqueous work up, the crudereaction mixture was purified by chromatography on silica using an 80:2mixture of hexanes:triethylamine to obtain 68 mg (20%) of the titlecompound as a colourless oily solid. ¹H NMR (500 MHz, THF-d₈) δ7.64-7.57 (m, 2H), 7.55 (dd, J=7.3, 1.8 Hz, 1H), 7.41 (ddd, J=8.3, 7.2,1.8 Hz, 1H), 7.15 (dd, J=8.3, 1.0 Hz, 1H), 7.14-7.09 (m, 2H), 4.34(Si—H) (p-like, J=1.2 Hz, 1H), 1.06-0.95 (m, 12H), 0.92-0.82 (m, 8H).¹³C NMR (126 MHz, THF-d₈) δ 166.04, 161.43, 139.74, 137.00, 135.55,135.05, 132.12, 130.19, 128.79, 123.56, 123.37, 118.41, 9.06, 7.93,6.70, 4.83. HRMS: [C₂₀H₂₇OSi₂] calculated 339.1601, measured 339.1607

A second fraction of the reaction mixture yielded 34 mg (39%) of thecyclized derivative. ¹H NMR (500 MHz, THF-d₈) δ 7.57-7.50 (m, 2H), 7.40(ddd, J=8.3, 7.2, 1.8 Hz, 2H), 7.15 (dd, J=8.6, 0.7 Hz, 2H), 7.11 (td,J=7.2, 1.0 Hz, 2H), 0.99-0.95 (m, 4H), 0.92-0.86 (m, 6H). ¹³C NMR (126MHz, THF-d₈) δ 161.54, 134.96, 132.07, 123.41, 118.80, 117.39, 7.95,6.72. HRMS: [C₁₆H₁₉OSi] calculated 255.1205, measured 255.1206. The HSQCspectra of these reaction products have previously been reported in U.S.Pat. No. 9,000,167.

A third fraction was obtained, containing a product in low yield (ca.7%) whose spectral characteristics appear to be consistent with thestructure of the monosilylated product shown above.

In a second set of experiments, when oxydibenzene was used as thesolvent, the reaction more cleanly produced the monosilylatedderivative, triethyl(2-phenoxyphenyl)silane 17b:

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), oxydibenzene (85.0 mg, 0.5 mmol),and Et₃SiH (240 μL, 1.5 mmol, 3 equiv) without solvent at 85° C. for 120h. The desired product 17b (84.5 mg, 55% yield) was obtained afterpurification by silica gel flash chromatography (100% hexanes) as acolorless oil. Rf=0.4 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.52-7.46 (m, 1H), 7.38-7.25 (m, 3H), 7.10 (t, J=7.4 Hz, 2H), 7.00 (d,J=7.9 Hz, 2H), 6.81 (d, J=8.1 Hz, 1H), 0.97 (t, J=7.9 Hz, 9H), 0.85 (q,J=7.9 Hz, 6H).

Example 6.7.4: Silylation of 1,4-dimethoxybenzene

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 1,4-dimethoxybenzene (69.1 mg, 0.5mmol), and Et₃SiH (240 μL, 1.5 mmol, 3 equiv), in 0.5 mL of THF at 65°C. for 72 h. The desired product 17c (53.1 mg, 42% yield) andbis-silylated byproduct SI-17c (16.1 mg, 8% yield) were obtained afterpurification by silica gel flash chromatography (100% hexanes).

(2,5-Dimethoxyphenyl)triethylsilane 17c

Colorless oil, Rf=0.5 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ 6.93 (d,J=3.1 Hz, 1H), 6.85 (dd, J=8.8, 3.1 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H),3.80 (s, 3H), 3.74 (s, 3H), 0.99-0.91 (m, 9H), 0.85-0.74 (m, 6H); ¹³CNMR (126 MHz, CDCl₃) δ 158.8, 153.3, 126.7, 122.2, 122.3, 114.1, 55.7,55.5, 7.6, 3.7; IR (Neat Film, NaCl) 2952, 2873, 1580, 1478, 1463, 1398,1272, 1220, 1177, 1050, 1026, 872, 800, 769, 732 cm⁻¹; HRMS (EI+) calc'dfor C₁₄H₂₄O₂Si [M+.]: 252.1546, found 252.1540.

(2,5-Dimethoxy-1,4-phenylene)bis(triethylsilane) SI-17c

White solid, Rf=0.8 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ 6.81 (s,2H), 3.75 (s, 6H), 0.95 (td, J=7.9, 0.9 Hz, 9H), 0.85-0.77 (m, 6H); ¹³CNMR (126 MHz, CDCl₃) δ 158.5, 127.1, 116.9, 55.6, 7.7, 3.8; IR (NeatFilm, NaCl) 2948, 2870, 1459, 1418, 1345, 1262, 1203, 1107, 1045, 999,868, 727, 700 cm⁻¹; HRMS (EI+) calc'd for C₂₀H₃₈Si₂O₂ [M+.]: 366.2410,found 366.2415.

Triethyl(2-methoxy-5-methylphenyl)silane 20

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 1-methoxy-4-methylbenzene 19 (61.0mg, 0.5 mmol), and Et₃SiH (240 μL, 1.5 mmol, 3 equiv) at 85° C. for 120h. The desired product 20 (38.5 mg, 32% yield) was obtained afterpurification by silica gel flash chromatography (100% hexanes) as acolorless oil. Rf=0.4 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.17-7.08 (m, 2H), 6.74 (dt, J=8.7, 1.3 Hz, 1H), 3.76 (s, 3H), 2.30 (s,3H), 0.97-0.92 (m, 9H), 0.85-0.79 (m, 6H); ¹³C NMR (126 MHz, CDCl₃) δ162.7, 136.7, 130.9, 129.2, 125.0, 109.5, 55.2, 20.8, 7.8, 3.7; IR (NeatFilm, NaCl) 2951, 2873, 1595, 1480, 1464, 1385, 1238, 1175, 1147, 1081,1034, 1004, 876, 806, 708 cm⁻¹; HRMS (EI+) calc'd for C₁₄H₂₄OSi [M+.]:236.1596, found 236.1598.

Example 6.7.5: Triethyl((phenylthio)methyl)silane

The reaction was conducted according to the General Procedure by heatingthioanisole (62 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2equiv) and Et₃SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL oftetrahydrofuran for 65 hours at 65° C. After aqueous work up, the crudereaction mixture was purified by chromatography on silica using hexanes(isochratic) to obtain 81 mg (68%) of the title compound as a colourlessoil. ¹H NMR (500 MHz, THF-d8) δ 7.31-7.26 (m, 2H), 7.25-7.19 (m, 2H),7.11-7.01 (m, 1H), 1.03 (t, J=7.9 Hz, 9H), 0.78-0.60 (m, 6H). ¹³C NMR(126 MHz, THF-d8) δ 140.73, 128.31, 125.69, 124.19, 13.01, 6.62, 3.06.HRMS: [C₁₃H₂₁SSi] calculated 237.1140, measured 237.1133. The HSQCspectra of the thioanisole and its reaction product have previously beenreported in U.S. Pat. No. 9,000,167.

Example 6.8: Experiments with C—N and C—S Heteroaryl Compounds atElevated Temperatures

Experiments were also conducted with C—N and C—S heteroaryl compounds.In the case of compounds comprising C—N bonds, reactivity appeared to besimilar to that seen for C—O bonds, and it is reasonably expected thatthe wide ranging methods used for the latter will result in results insimilar reactivity in the former:

In the case of compounds comprising C—S compounds, the methods appear togenerally result in complete desulfurization of the molecules, at leastunder the aggressive conditions of these experiments, reflecting thehigher reactivity of these types of substrates (but compare withExamples 6.9.34 to 38). This difference in reactivities may reflect thedifferences in bond energies between the C—O, C—N, and C—S bonds(compare C—X bond dissociation energies in phenol (111), aniline (104),and thiophenol (85, all in kcal/mol). Of particular interest is thedesulfurization of even hindered dibenzothiophenes under relatively mildconditions. In none of these conversions were single C—S productsdetected:

Example 6.9: Experiments with Heteroaryl Compounds at Ambient orNear-Ambient Temperatures

A series of experiments were done at ambient or near ambienttemperatures (65° C. or below) to test the regioselectivity of severalof the more reactive heteroaryl compounds. The test conditions andresults are shown below. Yields for all reactions are either byisolation (chromatography on silica gel, or bul-to-bulb distillation) orby GC-FID or NMR analysis using internal standard for quantification.Note that C-3 silylated heteroarenes were found in some cases to beprone to protodesilylation on silica gel. In these cases, bulb-to-bulbdistillation was used or, alternatively, silica gel chromatography withca. 3% triethyl amine added to the eluent, or a combination of bothmethods. Products were identified as indicated by ¹H, ¹³C NMR, andHeteronuclear Single Quantum Coherence (HSQC) spectroscopy, or GC-MS, ora combination of both, where possible using comparisons with authenticsamples.

Example 6.9.1: 1-methyl-2-(triethylsilyl)-1H-indole 2a

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-methylindole 1a (65.5 mg, 0.5mmol, 1 equiv) and Et₃SiH (243 μL, 1.5 mmol, 3 equiv) at 45° C. for 96h. C2:C3>20:1. The desired product 2a (95.6 mg, 78% yield) was obtainedas a colorless oil after purification by silica gel flash chromatography(gradient elution, 2→3% CH₂Cl₂ in hexanes). Rf=0.4 (10% CH₂Cl₂ inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.70 (dt, J=7.9, 1.1 Hz, 1H), 7.40(dq, J=8.3, 1.0 Hz, 1H), 7.30 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.16 (ddd,J=7.9, 6.9, 1.0 Hz, 1H), 6.81 (d, J=1.1 Hz, 1H), 3.90 (s, 3H), 1.13-1.05(m, 9H), 1.03-0.95 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 140.4, 138.3,128.7, 122.0, 120.7, 119.1, 113.1, 109.1, 33.1, 7.7, 4.2. IR (Neat Film,NaCl) 2953, 2909, 2874, 1492, 1464, 1415, 1372, 1356, 1299, 1233, 1166,1101, 1069, 1007, 973, 797 cm⁻¹; HRMS (ESI+) calc'd for C₁₅H₂₄NSi[M+H]+: 246.1673, found 246.1674. The HSQC spectrum of this reactionproduct has previously been reported in U.S. Pat. No. 9,000,167.

This material was also made at scale as follows. A 500 mL oven-driedSchlenk flask equipped with a stir bar and stoppered with a rubberseptum was evacuated and refilled once with argon. KOt-Bu (18.8 grams,167.9 mmols, 20 mol %) was weighed out on the bench and added to theflask under a strong flow of argon. The charged flask was then evacuatedand refilled with argon. 1-Methylindole (95% purity, AKSci, undistilled,yellow oil; 95.1 mL, 762.4 mmol, 1.0 equiv) and Et₃SiH (182.6 mL, 1142mmol, 1.5 equiv), which were previously degassed, were added through theseptum by syringe. The mixture was then cooled to −78° C. (dryice/acetone) and evacuated/backfilled with argon for three cycles. Thecooling bath was removed and the flask was allowed to warm to roomtemperature under a positive pressure of argon. The flask was thentransferred to a heating mantle set at 45° C. and stirred for 72 hours.The flask with the resultant deep red-purple solution was removed fromheating and allowed to cool to room temperature, diluted with anhydrousEt2O (50 mL) and filtered to remove solid residue. After the solvent wasremoved in vacuo, a stirbar was added and the transparent deep ambersolution was stirred under high vacuum (100 millitorr) for several hoursto remove remaining volatiles. The mixture was then subjected todistillation under vacuum. The desired product 2a was obtained as a paleyellow oil (141.88 g, 76% yield).

Example 6.9.2: 1-methyl-3-(triethylsilyl)-1H-indole

The reaction was conducted according to the General Procedure by heatingN-methylindole (66 mg, 0.5 mmol, 1 equiv.), KOt-Bu (56 mg, 0.5 mmol, 1equiv.) and Et₃SiH (88 microliters, 0.55 mmol, 1.1 equiv.) in 1 mL oftetrahydrofuran for 312 hours at 23° C. After aqueous work up, the crudereaction mixture was purified by chromatography on silica eluting with95:5 hexanes:NEt₃ (isochratic) to obtain 103 mg (84%) of the titlecompound as a colourless oil. ¹H NMR (500 MHz, THF-d8) δ 7.63 (dt,J=7.9, 1.0 Hz, 1H), 7.32 (dt, J=8.2, 0.9 Hz, 1H), 7.15 (s, 1H), 7.12(ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.01 (ddd, J=8.0, 7.0, 1.1 Hz, 1H), 3.78(s, 3H), 1.06-0.95 (m, 9H), 0.95-0.83 (m, 6H). ¹³C NMR (126 MHz, THF-d8)δ 138.63, 135.94, 133.37, 121.44, 120.88, 118.79, 108.96, 104.39, 31.61,7.04, 4.11. The HSQC spectrum of this reaction product has previouslybeen reported in U.S. Pat. No. 9,000,167.

Example 6.9.3: 1-methyl-3-(triethylsilyl)-1H-indole 2b

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-benzylindole 1b (103.5 mg, 0.5mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at45° C. for 40 h. C2:C3>20:1. The desired product 2b (132.2 mg, 82%yield) was obtained as a colorless oil after purification by silica gelflash chromatography (10% CH₂Cl₂ in hexanes). Rf=0.3 (10% CH₂Cl₂ inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.81-7.77 (m, 1H), 7.38-7.29 (m,3H), 7.26-7.19 (m, 3H), 7.02 (ddd, J=6.9, 2.2, 1.0 Hz, 2H), 6.97 (s,1H), 5.59 (s, 2H), 1.08-1.04 (m, 9H), 0.94-0.89 (m, 6H); ¹³C NMR (125MHz, CDCl₃) δ 140.2, 138.5, 138.3, 129.1, 128.7, 127.3, 125.9, 122.3,120.7, 119.5, 114.1, 110.2, 50.2, 7.5, 4.0. IR (Neat Film, NaCl) 3060,3029, 2954, 2909, 2875, 1606, 1495, 1466, 1452, 1416, 1377, 1353, 1333,1300, 1238, 1196, 1164, 1115, 1096, 1014, 798, 734 cm⁻¹; HRMS (ESI+)calc'd for C21H28NSi [M+H]+: 322.1986, found 322.1985.

The reaction was conducted according to the General Procedure by heating1-benzylindole (62 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2equiv) and Et₃SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL oftetrahydrofuran for 48 hours at 23° C. After aqueous work up, the crudereaction mixture was purified by chromatography on silica using hexanes(isochratic) to obtain 50 mg (31%) of the title compound as a colourlessoily solid. ¹H NMR (500 MHz, THF-d8) δ 7.56 (ddd, J=7.7, 1.3, 0.7 Hz,1H), 7.25-7.07 (m, 4H), 7.02 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 6.98 (ddd,J=7.9, 6.9, 1.1 Hz, 1H), 6.92-6.86 (m, 2H), 6.80 (d, J=0.9 Hz, 1H), 5.52(s, 2H), 1.06-0.88 (m, 9H), 0.85-0.69 (m, 6H).

Example 6.9.4: 1-Ethyl-2-(triethylsilyl)-1H-indole 2c

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-ethylindole 1c (72.5 mg, 0.5mmol, 1 equiv), and Et₃SiH (243 μL, 1.5 mmol, 3 equiv) at 60° C. for 84h. C2:C3>20:1. The desired product 2c (92.4 mg, 71% yield) was obtainedas a colorless oil after purification by silica gel flash chromatography(5% CH₂Cl₂ in hexanes). Rf=0.4 (10% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.67 (dt, J=7.9, 0.9 Hz, 1H), 7.40 (dt, J=8.2, 0.9 Hz, 1H),7.25 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.13 (ddd, J=7.9, 7.0, 1.0 Hz, 1H),6.75 (d, J=1.0 Hz, 1H), 4.31 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H),1.08-1.04 (m, 9H), 0.99-0.92 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 139.0,137.4, 129.1, 121.7, 120.7, 119.0, 113.0, 109.4, 41.5, 15.5, 7.5, 4.0.IR (Neat Film, NaCl) 2953, 2909, 2874, 1491, 1466, 1416, 1378, 1347,1335, 1299, 1218, 1165, 1090, 1069, 1012, 956, 900, 820, 787, 773, 750,733 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₁₆H₂₆NSi [M+H]+: 260.1829,found 260.1829.

Example 6.9.5: 1-Phenyl-2-(triethylsilyl)-1H-indole 2d

The reaction was conducted according to the General Procedure by heatingKOt-Bu (7.4 mg, 0.07 mmol, 20 mol %), N-phenylindole 1d (63.2 mg, 0.33mmol, 1 equiv), and Et₃SiH (160 μL, 1.0 mmol, 3 equiv) at 60° C. for 84h. C2:C3>20:1. The desired product 2d (45.6 mg, 45% yield) was obtainedas a white solid after purification by silica gel flash chromatography(3% CH₂Cl₂ in hexanes). Rf=0.5 (10% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.74-7.67 (m, 1H), 7.58-7.47 (m, 3H), 7.44-7.36 (m, 2H),7.21-7.12 (m, 2H), 7.12-7.05 (m, 1H), 6.93 (d, J=0.9 Hz, 1H), 0.92 (t,J=7.9 Hz, 9H), 0.68-0.55 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 141.6,140.8, 139.1, 129.2, 128.8, 128.7, 128.3, 122.4, 120.5, 119.8, 114.9,110.5, 7.5, 4.0. IR (Neat Film, NaCl) 3058, 2952, 2909, 2873, 1597,1498, 1465, 1428, 1362, 1297, 1237, 1214, 1122, 1071, 1012, 976, 922,820, 793, 736 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₂₀H₂₆NSi [M+H]+:308.1829, found 308.1824.

Example 6.9.6: 1-(Methoxymethyl)-2-(triethylsilyl)-1H-indole 2e

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), Nmethoxymethylindole 1e (80.5 mg,0.5 mmol, 1 equiv) and Et₃SiH (243 μL, 1.5 mmol, 3 equiv) at 60° C. for84 h. C2:C3=10:1. The desired product 2e (75.1 mg, 55% yield) wasobtained as a colorless oil after purification by silica gel flashchromatography (3% EtOAc in hexanes). Rf=0.3 (5% EtOAc in hexanes); ¹HNMR (500 MHz, CDCl₃) δ 7.67 (dt, J=7.8, 1.0 Hz, 1H), 7.53 (dq, J=8.3,0.9 Hz, 1H), 7.28 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 7.17 (ddd, J=7.9, 7.0,1.0 Hz, 1H), 6.86 (d, J=0.9 Hz, 1H), 5.55 (s, 2H), 3.30 (s, 3H),1.10-1.01 (m, 9H), 1.01-0.92 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 140.7,138.3, 129.2, 122.6, 120.8, 120.0, 115.6, 109.8, 76.8, 55.6, 7.5, 4.1.IR (Neat Film, NaCl) 2952, 2908, 2874, 1495, 1466, 1416, 1393, 1344,1311, 1299, 1224, 1166, 1126, 1104, 1091, 1045, 1004, 961, 913, 797,762, 735 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₁₆H₂₆NOSi [M+H]+:276.1778, found 276.1769.

Example 6.9.7:2-(Triethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole 2f

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %),N-(2-trimethylsilyl-ethoxymethyl)-1H-indole 1f (123.5 mg, 0.5 mmol, 1equiv) and Et₃SiH (243 μL, 1.5 mmol, 3 equiv) at 60° C. for 84 h.C2:C3>20:1. The desired product 2f (121.4 mg, 67% yield) was obtained asa colorless oil after purification by silica gel flash chromatography(15% CH₂Cl₂ in hexanes). Rf=0.2 (10% CH₂Cl₂ in hexanes); ¹H NMR (500MHz, CDCl₃) δ 7.62 (dt, J=7.8, 1.0 Hz, 1H), 7.50 (dq, J=8.3, 0.9 Hz,1H), 7.24 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 7.12 (ddd, J=7.9, 7.0, 0.9 Hz,1H), 6.80 (d, J=0.9 Hz, 1H), 5.54 (s, 2H), 3.54-3.48 (m, 2H), 1.04-0.98(m, 9H), 0.96-0.90 (m, 8H), −0.02 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ140.5, 138.1, 129.1, 122.4, 120.7, 119.9, 115.3, 109.8, 75.2, 65.6,18.1, 7.6, 4.0, −1.3. IR (Neat Film, NaCl) 2952, 2875, 1495, 1466, 1443,1417, 1378, 1343, 1312, 1299, 1249, 1167, 1081, 1003, 972, 939, 894,859, 836, 796, 760, 749, 734 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd forC₂₀H₃₆NOSi₂ [M+H]+: 362.2330, found 362.2340.

Example 6.9.8: Reaction of 4-methyl-N-methylindole with Et₃SiH

The reaction was conducted according to the General Procedure. Forcondition A: The reaction was performed with KOt-Bu (11.2 mg, 0.1 mmol,20 mol %), 4-methyl-N-methylindole 1g (72.5 mg, 0.5 mmol, 1 equiv),Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 25° C. for 120h. C2:C3>20:1. The desired mono-silylation product 2g (61.8 mg, 48%yield) and bis-silylation 16 (9.7 mg, 5% yield) were obtained afterpurification by silica gel flash chromatography (gradient elution, 2→3%CH₂Cl₂ in hexanes). For condition B: The reaction was performed withKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 4-methyl-Nmethylindole 1g (72.5mg, 0.5 mmol, 1 equiv) and Et₃SiH (243 μL, 1.5 mmol, 3 equiv) at 45° C.for 84 h. C2:C3>20:1. Only mono silylation product 2g (89.7 mg, 69%yield) was formed and obtained after purification by silica gel flashchromatography (3% CH₂Cl₂ in hexanes).

1,4-Dimethyl-2-(triethylsilyl)-1H-indole 2g

Colorless oil; Rf=0.4 (10% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.23-7.14 (m, 2H), 6.91 (dt, J=6.7, 1.0 Hz, 1H), 6.75 (d, J=0.9 Hz, 1H),3.85 (s, 3H), 2.60 (s, 3H), 1.07-1.00 (m, 9H), 0.98-0.92 (m, 6H); ¹³CNMR (125 MHz, CDCl₃) δ 140.2, 137.6, 130.2, 128.6, 122.2, 119.4, 111.5,106.8, 33.2, 18.8, 7.7, 4.3. IR (Neat Film, NaCl) 2953, 2910, 2874,1586, 1502, 1454, 1415, 1366, 1323, 1280, 1238, 1160, 1140, 1077, 1004,953, 765, 752, 735 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₁₆H₂₆NSi[M+H]+: 260.1829, found 260.1823.

1-Methyl-2-(triethylsilyl)-4-((triethylsilyl)methyl)-1H-indole 16

Colorless oil; Rf=0.4 (10% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, C6D6) δ7.28 (dd, J=8.2, 7.1 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.97-6.94 (m, 2H),3.31 (s, 3H), 2.50 (s, 2H), 1.01 (t, J=7.8 Hz, 9H), 0.95 (t, J=7.9 Hz,9H), 0.83 (q, J=7.8 Hz, 6H), 0.58 (q, J=7.9 Hz, 6H); ¹³C NMR (125 MHz,C6D6) δ 141.1, 136.0, 133.3, 122.8, 118.9, 113.0, 105.8, 32.9, 19.2,7.7, 4.5, 4.1. IR (Neat Film, NaCl) 2952, 2909, 2874, 1579, 1498, 1454,1443, 1414, 1359, 1322, 1285, 1237, 1151, 1070, 1008, 980, 774, 734cm⁻¹; HRMS (EI+) calc'd for C₂₂H₃₉NSi₂ [M.+]: 373.2621, found 373.2624.

Example 6.9.9: 1,5-Dimethyl-2-(triethylsilyl)-1H-indole 2h

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 5-methyl-N-methylindole 1h (72.5mg, 0.5 mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mLof THF at 25° C. for 96 h. C2:C3>20:1. The desired product 2h (88.7 mg,68% yield) was obtained as a colorless oil after purification by silicagel flash chromatography (10% CH₂Cl₂ in hexanes). Rf=0.3 (10% CH₂Cl₂ inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.39 (s, 1H), 7.25-7.19 (m, 1H),7.05 (dd, J=8.4, 1.6 Hz, 1H), 6.63 (d, J=0.8 Hz, 1H), 3.81 (s, 3H), 2.45(s, 3H), 1.03-0.97 (m, 9H), 0.93-0.86 (m, 6H). ¹³C NMR (125 MHz, CDCl₃)δ 138.8, 138.3, 128.9, 128.3, 123.6, 120.2, 112.4, 108.8, 33.1, 21.5,7.7, 4.1. IR (Neat Film, NaCl) 2952, 2909, 2873, 1505, 1456, 1358, 1321,1236, 1181, 1104, 1069, 1003, 833, 788, 736 cm⁻¹; HRMS (ESI+) calc'd forC₁₆H₂₆NSi [M+H]+: 260.1826, found 260.1827.

Example 6.9.10: Reaction of 5-methyl-Nmethyl indole with Et₃SiH

The reaction was conducted according to the General Procedure. Forcondition A: The reaction was performed with KOt-Bu (11.2 mg, 0.1 mmol,20 mol %), 6-methyl-N-methylindole 1i (72.5 mg, 0.5 mmol, 1 equiv),Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 25° C. for 120h. C2:C3>20:1. The desired mono silylation product 2i (69.5 mg, 54%yield) and bis-silylation SI-2i (5.2 mg, 3% yield) were obtained afterpurification by silica gel flash chromatography (gradient elution, 2→3%CH₂Cl₂ in hexanes). For condition B: The reaction was performed withKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 6-methyl-N-methylindole 1i (72.5mg, 0.5 mmol, 1 equiv) and Et₃SiH (243 μL, 1.5 mmol, 3 equiv) at 45° C.for 84 h. C2:C3>20:1. Only mono silylation product 2i (108.1 mg, 83%yield) was formed and obtained after purification by silica gel flashchromatography (3% CH₂Cl₂ in hexanes).

1,6-Dimethyl-2-(triethylsilyl)-1H-indole 2i

Colorless oil; Rf=0.4 (10% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.55 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 6.98 (ddd, J=8.0, 1.4, 0.7 Hz,1H), 6.73 (d, J=0.9 Hz, 1H), 3.85 (s, 3H), 2.57 (s, 3H), 1.08-1.03 (m,9H), 0.98-0.92 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 140.9, 137.6, 131.8,126.7, 121.0, 120.3, 113.0, 109.1, 33.0, 22.0, 7.6, 4.2. IR (Neat Film,NaCl) 2953, 2910, 2874, 1617, 1480, 1451, 1413, 1376, 1360, 1333, 1296,1233, 1065, 1003, 941, 808, 781, 736 cm⁻¹; HRMS (ESI+) calc'd forC₁₆H₂₆NSi [M+H]+: 260.1826, found 260.1823.

1-Methyl-2-(triethylsilyl)-6-((triethylsilyl)methyl)-1H-indole SI-2i

Colorless oil; Rf=0.4 (10% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, C6D6) δ7.64 (dd, J=7.9, 0.8 Hz, 1H), 6.99-6.93 (m, 2H), 6.81 (d, J=0.9 Hz, 1H),3.41 (s, 3H), 2.31 (s, 2H), 1.02-0.93 (m, 18H), 0.79 (q, J=7.7 Hz, 6H),0.58 (q, J=7.9 Hz, 6H); ¹³C NMR (125 MHz, C₆D6) δ 141.9, 136.3, 134.6,126.7, 121.2, 120.9, 114.0, 108.3, 32.7, 22.4, 7.8, 7.7, 4.5, 3.7. IR(Neat Film, NaCl) 2952, 2909, 2874, 1615, 1568, 1479, 1463, 1414, 1361,1336, 1319, 1299, 1234, 1195, 1157, 1090, 1065, 1009, 948, 842, 817,787, 771, 736 cm⁻¹; HRMS (EI+) calc'd for C₂₂H₃₉NSi₂ [M.+]: 373.2621,found 373.2609.

Example 6.9.11: 1,7-Dimethyl-2-(triethylsilyl)-1H-indole 2j

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 7-methyl-Nmethylindole 1j (72.5mg, 0.5 mmol, 1 equiv) and Et₃SiH (243 μL, 1.5 mmol, 3 equiv) at 45° C.for 84 h. C2:C3>20:1. The desired product 2j (78.9 mg, 61% yield) wasobtained as a colorless oil after purification by silica gel flashchromatography (3% CH₂Cl₂ in hexanes). Rf=0.4 (10% CH₂Cl₂ in hexanes);¹H NMR (500 MHz, CDCl₃) δ 7.43 (d, J=7.7 Hz, 1H), 6.94-6.87 (m, 2H),6.66 (s, 1H), 4.11 (s, 3H), 2.80 (s, 3H), 1.03-0.97 (m, 9H), 0.92-0.85(m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 139.2, 139.1, 129.7, 125.0, 121.0,119.4, 119.0, 113.6, 36.8, 20.6, 7.7, 4.2. IR (Neat Film, NaCl) 2953,2909, 2873, 1503, 1459, 1415, 1396, 1377, 1358, 1340, 1315, 1304, 1238,1156, 1113, 1086, 1063, 1004, 861, 798, 742 cm⁻¹; HRMS (ESI+) calc'd forC₁₆H₂₆NSi [M+H]+: 260.1826, found 260.1828.

Example 6.9.12: Reaction of N-methyl-5-methoxyindole 1k with Et₃SiH

The reaction was conducted according to the General Procedure. Forcondition A: The reaction was performed with KOt-Bu (11.2 mg, 0.1 mmol,20 mol %), N-methyl-5-methoxyindole 1k (80.7 mg, 0.5 mmol, 1 equiv),Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 25° C. for 120h. C2:C3>20:1. The C2-silylation product 2k (58.7 mg, 43% yield),C6-silylation product 15 (12.5 mg, 9% yield), and bis-silylation productSI-2k (42.9 mg, 22% yield), were obtained after purification by silicagel flash chromatography (gradient elution, 5→10→25% CH₂Cl₂ in hexanes).For condition B: The reaction was performed with KOt-Bu (11.2 mg, 0.1mmol, 20 mol %), N-methyl-5-methoxyindole 1k (80.5 mg, 0.5 mmol, 1equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 25° C.for 72 h. C2:C3>20:1. The desired product 2k (87.6 mg, 64% yield) wasobtained after purification by silica gel flash chromatography (gradientelution, 5→10→25% CH₂Cl₂ in hexanes) and a minor amount (<5%) ofbyproducts were observed.

5-Methoxy-1-methyl-2-(triethylsilyl)-1H-indole 2k

White solid; Rf=0.2 (33% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.21 (s, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.89 (dd, J=8.8, 2.5 Hz, 1H), 6.63(d, J=0.8 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 1.03-0.96 (m, 9H),0.93-0.86 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 154.0, 139.0, 135.9,128.8, 112.6, 112.3, 109.8, 102.0, 56.1, 33.2, 7.7, 4.1. IR (Neat Film,NaCl) 2950, 2909, 2872, 1503, 1450, 1413, 1334, 1237, 1208, 1173, 1147,1102, 1072, 1027, 997, 843, 801, 735, 716 cm⁻¹; HRMS (ESI+) calc'd forC₁₆H₂₆NOSi [M+H]+: 276.1778, found 276.1776.

5-Methoxy-1-methyl-2,6-bis(triethylsilyl)-1H-indole SI-2k

White solid, Rf=0.6 (33% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.30 (s, 1H), 7.01 (s, 1H), 6.64 (d, J=0.8 Hz, 1H), 3.85 (s, 3H), 3.83(s, 3H), 1.06-0.97 (m, 18H), 0.95-0.86 (m, 12H); ¹³C NMR (125 MHz,CDCl₃) δ 159.1, 138.9, 136.1, 130.1, 120.8, 116.3, 112.2, 99.7, 55.5,33.2, 7.9, 7.7, 4.3, 4.1. IR (Neat Film, NaCl) 2952, 2874, 2908, 1608,1556, 1475, 1454, 1407, 1363, 1337, 1236, 1205, 1172, 1144, 1123, 1072,1004, 971, 837 cm⁻¹; HRMS (ESI+) calc'd for C₂₂H₄₀NOSi₂ [M+H]+:390.2643, found 390.2632.

5-Methoxy-1-methyl-6-(triethylsilyl)-1H-indole 15

Colorless oil; Rf=0.4 (33% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.27 (s, 1H), 7.01 (s, 1H), 7.00 (d, J=3.0 Hz, 1H), 6.38 (dd, J=3.0, 0.8Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 1.00-0.94 (m, 9H), 0.91-0.83 (m,6H); ¹³C NMR (125 MHz, CDCl₃) δ 159.2, 132.5, 130.1, 129.3, 120.2,116.5, 100.4, 100.3, 55.5, 33.0, 7.9, 4.1. IR (Neat Film, NaCl) 2950,2908, 2873, 1612, 1554, 1505, 1471, 1414, 1310, 1268, 1231, 1190, 1148,1123, 1059, 1017, 984, 831 cm⁻¹; HRMS (ESI+) calc'd for C₁₆H₂₆NOSi[M+H]+: 276.1778, found 276.1765.

Example 6.9.13: 5-(Benzyloxy)-1-methyl-2-(triethylsilyl)-1H-indole 2l

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-methyl-5-benzyloxyindole 1l(118.5 mg, 0.5 mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and0.5 mL of THF at 45° C. for 64 h. C2:C3>20:1. The desired product 2l(119.4 mg, 68% yield) was obtained as a yellow solid after purificationby silica gel flash chromatography (25% CH₂Cl₂ in hexanes). Rf=0.4 (5%EtOAc in hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.48 (d, J=7.0 Hz, 2H),7.41-7.36 (m, 2H), 7.35-7.29 (m, 1H), 7.22 (d, J=8.9 Hz, 1H), 7.14 (d,J=2.4 Hz, 1H), 6.97 (dd, J=8.8, 2.4 Hz, 1H), 6.62 (d, J=0.8 Hz, 1H),5.11 (s, 2H), 3.81 (s, 3H), 1.04-0.96 (m, 9H), 0.96-0.84 (m, 6H); ¹³CNMR (125 MHz, CDCl₃) δ 153.3, 139.1, 138.1, 136.2, 129.0, 128.6, 127.8,127.6, 113.4, 112.5, 109.8, 104.0, 71.3, 33.2, 7.6, 4.2. IR (Neat Film,NaCl) 2951, 2908, 2872, 1492, 1452, 1422, 1336, 1288, 1237, 1192, 1150,1102, 1075, 1018, 840, 812, 751, 735 cm⁻¹; HRMS (MM: ESI-APCI+) calc'dfor C₂₂H₃₀NOSi [M+H]+: 352.2091, found 352.2093.

Example 6.9.14: Reaction of 5-(methoxymethyl)-N-methylindole 1m withEt₃SiH

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 5-(methoxymethyl)-N-methylindole1m (87.5 mg, 0.5 mmol, 1 equiv) and Et₃SiH (243 μL, 1.5 mmol, 3 equiv)at 45° C. for 84 h. C2:C3>20:1. The desired product 2m (69.3 mg, 48%yield), byproducts 1h (2.5 mg, 2% yield) and 2h (11.3 mg, 9% yield) wereobtained after purification by silica gel flash chromatography (gradientelution, 25→50% CH₂Cl₂ in hexanes).

5-(Methoxymethyl)-1-methyl-2-(triethylsilyl)-1H-indole 2m

Colorless oil, Rf=0.4 (50% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.59 (d, J=0.8 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H),6.73 (d, J=0.8 Hz, 1H), 4.59 (s, 2H), 3.85 (s, 3H), 3.38 (s, 3H),1.06-0.99 (m, 9H), 0.96-0.90 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 140.0,138.9, 128.8, 128.5, 122.6, 120.5, 113.0, 109.1, 75.6, 57.6, 33.2, 7.6,4.1. IR (Neat Film, NaCl) 2952, 2873, 2817, 1504, 1455, 1415, 1357,1324, 1297, 1236, 1188, 1153, 1137, 1094, 1069, 1004, 971, 878, 840,798, 783, 726 cm⁻¹; HRMS (ESI+) calc'd for C₁₇H₂₈NOSi [M+H]+: 290.1935,found 290.1948.

Example 6.9.15: 1-Methyl-5-phenyl-2-(triethylsilyl)-1H-indole 2n

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 5-phenyl-N-methylindole 1n (103.5mg, 0.5 mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mLof THF at 45° C. for 108 h. C2:C3>20:1. The desired product 2n (77.8 mg,48% yield) was obtained as a white solid after purification by silicagel flash chromatography (gradient elution, 5→10% CH₂Cl₂ in hexanes).Rf=0.3 (10% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.90 (s, 1H),7.72 (d, J=7.6 Hz, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.53-7.47 (m, 2H), 7.44(d, J=8.5 Hz, 1H), 7.37 (t, J=7.4 Hz, 1H), 6.85 (s, 1H), 3.91 (s, 3H),1.09 (t, J=7.8 Hz, 9H), 1.03-0.95 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ142.9, 140.0, 139.3, 132.8, 129.2, 128.7, 127.5, 126.3, 122.0, 119.2,113.5, 109.4, 33.2, 7.6, 4.2. IR (Neat Film, NaCl) 2950, 2908, 2873,1600, 1485, 1455, 1361, 1325, 1301, 1214, 1162, 1074, 1004, 1086, 887,820, 807, 787, 759, 733 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₂₁H₂₈NSi[M+H]+: 322.1986, found 322.1984.

Example 6.9.16: Reaction of N-methylindole 1a with Et₂SiH₂

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-methylindole 1a (65.5 mg, 0.5mmol, 1 equiv), Et₂SiH₂ (194 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THFat 45° C. for 72 h. C2:C3>20:1. The silylation product 2o (73.4 mg, 68%yield) and a minor bisindolyl silane byproduct SI-2o were obtained afterpurification by silica gel flash chromatography (gradient elution,1→2→5% CH₂Cl₂ in hexanes).

2-(Diethylsilyl)-1-methyl-1H-indole 2o

Colorless oil; Rf=0.4 (10% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.66 (dt, J=7.9, 1.0 Hz, 1H), 7.37 (dt, J=8.3, 1.1 Hz, 1H), 7.28-7.25(m, 1H), 7.16-7.09 (m, 1H), 6.79 (d, J=0.9 Hz, 1H), 4.50-4.43 (m, 1H),3.88 (s, 3H), 1.14-1.06 (m, 6H), 1.00-0.93 (m, 4H); ¹³C NMR (125 MHz,CDCl₃) δ 140.2, 136.6, 128.6, 122.2, 120.8, 119.3, 112.8, 109.3, 32.8,8.4, 3.7. IR (Neat Film, NaCl) 2954, 2908, 2872, 2110, 1492, 1464, 1412,1371, 1357, 1327, 1301, 1233, 1166, 1101, 1071, 1009, 974, 987, 815, 785cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C13H20NSi [M+H]+: 218.1360, found218.1354.

Diethylbis(1-methyl-1H-indol-2-yl)silane SI-2o

Colorless oil; Rf=0.2 (10% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.68 (dt, J=7.9, 1.0 Hz, 2H), 7.31 (dt, J=8.3, 1.0 Hz, 2H), 7.25 (ddd,J=8.2, 6.9, 1.2 Hz, 2H), 7.13 (ddd, J=7.9, 6.9, 1.1 Hz, 2H), 6.92 (d,J=0.9 Hz, 2H), 3.57 (s, 6H), 1.31 (q, J=8.4 Hz, 4H), 1.07 (t, J=7.9 Hz,6H); ¹³C NMR (125 MHz, CDCl₃) δ 140.7, 136.5, 128.7, 122.5, 120.9,119.4, 113.8, 109.4, 32.7, 7.5, 4.5. IR (Neat Film, NaCl) 2955, 2874,1492, 1463, 1414, 1355, 1327, 1299, 1233, 1166, 1101, 1072, 1008, 799,751 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₂₂H₂₇N₂Si [M+H]+: 347.1938,found 347.1934.

Example 6.9.17: 1-Benzyl-2-(diethylsilyl)-1H-indole 2p

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-benzyl indole 1b (103.5 mg, 0.5mmol, 1 equiv) and Et₂SiH₂ (194 μL, 1.5 mmol, 3 equiv) at 60° C. for 72h. C2:C3>20:1. The desired product 2p (114.1 mg, 78% yield) was obtainedas a colorless oil after purification by silica gel flash chromatography(5% CH₂Cl₂ in hexanes). Rf=0.5 (25% CH₂Cl₂ in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 7.75 (dt, J=7.7, 1.0 Hz, 1H), 7.36-7.26 (m, 4H), 7.26-7.15 (m,2H), 7.07-7.01 (m, 2H), 6.94 (d, J=0.9 Hz, 1H), 5.56 (s, 2H), 4.44 (p,J=3.3 Hz, 1H), 1.12-1.03 (m, 6H), 0.94-0.79 (m, 4H). ¹³C NMR (125 MHz,CDCl₃) δ 140.1, 138.5, 136.7, 129.0, 128.7, 127.4, 126.1, 122.5, 120.8,119.6, 113.7, 110.1, 49.8, 8.3, 3.6. IR (Neat Film, NaCl) 2954, 2873,2114, 1605, 1494, 1466, 1450, 1413, 1353, 1334, 1301, 1233, 1198, 1164,1116, 1095, 972, 815 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₁₉H₂₄NSi[M+H]+: 294.1673, found 294.1668.

Example 6.9.18: 2-(Diethylsilyl)-1-phenyl-1H-indole 2q

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-phenyl indole 1d (96.5 mg, 0.5mmol, 1 equiv), Et₂SiH₂ (194 μL, 1.5 mmol, 3 equiv), and 0.5 mL ofMeOt-Bu at 55° C. for 96 h. C2:C3>20:1. The desired product 2q (76.9 mg,55% yield) was obtained as a yellow oil after purification by silica gelflash chromatography (10% CH₂Cl₂ in hexanes). Rf=0.6 (10% CH₂Cl₂ inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.76-7.74 (m, 1H), 7.60-7.55 (m,2H), 7.53-7.47 (m, 3H), 7.30-7.17 (m, 3H), 7.03 (d, J=0.9 Hz, 1H), 4.30(p, J=3.3 Hz, 1H), 1.02-0.98 (m, 6H), 0.79-0.63 (m, 4H); ¹³C NMR (125MHz, CDCl₃) δ 141.1, 140.3, 137.1, 129.4, 128.8, 128.1, 128.0, 122.8,120.7, 120.1, 115.1, 110.5, 8.2, 3.4. IR (Neat Film, NaCl) 3058, 2953,2872, 2117, 1597, 1498, 1466, 1433, 1415, 1363, 1300, 1215, 1202, 1146,1121, 1072, 1013, 978, 921, 902, 823, 759, 748, 737 cm⁻¹; HRMS (MM:ESI-APCI+) calc'd for C₁₈H₂₂NSi [M+H]+: 280.1516, found 280.1515.

Example 6.9.19: 2-(Diethylsilyl)-1-(methoxymethyl)-1H-indole 2r

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-methoxymethylindole 1e (80.5 mg,0.5 mmol, 1 equiv) and Et₂SiH₂ (193 μL, 1.5 mmol, 3 equiv) at 60° C. for96 h. C2:C3>20:1. The desired product 2r (81.0 mg, 66% yield) wasobtained as a colorless oil after purification by silica gel flashchromatography (3% EtOAc in hexanes). Rf=0.3 (5% EtOAc in hexanes); ¹HNMR (500 MHz, CDCl₃) δ 7.67 (dt, J=7.9, 1.0 Hz, 1H), 7.54 (ddd, J=8.3,2.0, 0.9 Hz, 1H), 7.29 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 7.18 (ddd, J=7.9,7.0, 1.0 Hz, 1H), 6.88 (d, J=0.9 Hz, 1H), 5.60 (s, 2H), 4.49 (p, J=3.3Hz, 1H), 3.29 (s, 3H), 1.14-1.08 (m, 6H), 1.03-0.94 (m, 4H); ¹³C NMR(125 MHz, CDCl₃) δ 140.4, 136.6, 129.2, 122.8, 120.9, 120.2, 115.1,109.9, 76.6, 55.6, 8.3, 3.8. IR (Neat Film, NaCl) 2954, 2874, 2819,2115, 1496, 1467, 1443, 1413, 1393, 1360, 1344, 1314, 1300, 1282, 1226,1190, 1166, 1127, 1102, 1091, 1047, 1009, 974, 914, 896, 818, 749, 736cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₁₄H₂₂NOSi [M+H]+: 248.1465, found248.1459.

Example 6.9.20:2-(Diethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole 2s

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %),N-(2-trimethylsilyl-ethoxymethyl)-1H-indole 1f (123.5 mg, 0.5 mmol, 1equiv) and Et₂SiH₂ (194 μL, 1.5 mmol, 3 equiv) at 60° C. for 84 h.C2:C3>20:1. The desired product 2s (106.7 mg, 64% yield) was obtainedafter purification by silica gel flash chromatography (14% CH₂Cl₂ inhexanes) as a colorless oil. Rf=0.2 (10% CH₂Cl₂ in hexanes); ¹H NMR (500MHz, CDCl₃) δ 7.65 (dt, J=7.9, 1.0 Hz, 1H), 7.53 (dt, J=8.3, 0.9 Hz,1H), 7.27 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 7.15 (ddd, J=7.9, 7.0, 0.9 Hz,1H), 6.84 (d, J=0.8 Hz, 1H), 5.61 (s, 2H), 4.48 (p, J=3.3 Hz, 1H),3.55-3.48 (m, 2H), 1.14-1.04 (m, 6H), 1.03-0.88 (m, 6H), −0.02 (s, 9H);¹³C NMR (125 MHz, CDCl₃) δ 140.2, 136.5, 129.1, 122.7, 120.8, 120.1,114.7, 110.1, 75.0, 65.6, 18.0, 8.4, 3.7, −1.3. IR (Neat Film, NaCl)2953, 2874, 2116, 1496, 1466, 1443, 1413, 1379, 1343, 1318, 1300, 1249,1219, 1165, 1081, 1010, 974, 922, 895, 859, 835, 748, 735 cm⁻¹; HRMS(MM: ESIAPCI+) calc'd for C₁₈H₃₂NOSi₂ [M+H]+: 334.2017, found 334.2028.

Example 6.9.21: 2-(Diethylsilyl)-1,3-dimethyl-1H-indole 2t

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 1,3-dimethyl-1H-indole 1t (72.6mg, 0.5 mmol, 1 equiv), Et₂SiH₂ (193 μL, 1.5 mmol, 3 equiv), and 0.5 mLof THF at 65° C. for 120 h. The desired product 2t (84.2 mg, 65% yield)was obtained as a colorless oil after purification by silica gel flashchromatography (100% hexanes). Rf=0.6 (100% hexanes); ¹H NMR (500 MHz,C₆D6) δ 7.67 (d, J=7.9 Hz, 1H), 7.30 (dd, J=8.3, 6.9 Hz, 1H), 7.22 (t,J=7.4 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 4.59 (p, J=3.7 Hz, 1H), 3.31 (s,3H), 2.46 (s, 3H), 0.98 (t, J=7.8 Hz, 6H), 0.77 (qd, J=7.9, 3.9 Hz, 4H);¹³C NMR (125 MHz, C₆D6) δ 140.6, 131.5, 129.8, 122.7, 122.3, 119.4,119.0, 109.4, 32.4, 10.9, 8.8, 4.7. IR (Neat Film, NaCl) 2952, 2871,2125, 1509, 1460, 1351, 1317, 1237, 1167, 1138, 1011, 975, 839, 803, 737cm⁻¹; HRMS (EI+) calc'd for C₁₄H₂₁NSi [M.+]: 231.1443, found 231.1446.

Example 6.9.22: 2-(Ethyldimethylsilyl)-1-methyl-1H-indole 2u

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-methylindole 1a (66.8 mg, 0.5mmol, 1 equiv), EtMe₂SiH (197 μL, 1.5 mmol, 3 equiv) and 0.5 mL ofMeOt-Bu at 45° C. for 120 h. C2:C3>20:1. The desired product 2u (58.5mg, 54% yield) was obtained as a colorless oil after purification bysilica gel flash chromatography (3% CH₂Cl₂ in hexanes). Rf=0.4 (10%CH₂Cl₂ in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.67 (dt, J=7.8, 1.0 Hz,1H), 7.37 (dd, J=8.3, 0.9 Hz, 1H), 7.28 (ddd, J=8.2, 6.9, 1.1 Hz, 1H),7.14 (ddd, J=7.9, 6.9, 1.0 Hz, 1H), 6.77 (d, J=0.9 Hz, 1H), 3.89 (s,3H), 1.11-1.02 (m, 3H), 0.95-0.90 (m, 2H), 0.43 (s, 6H); ¹³C NMR (125MHz, CDCl₃) δ 140.3, 140.2, 128.5, 122.1, 120.7, 119.2, 112.0, 109.1,33.1, 7.8, 7.6, −2.6. IR (Neat Film, NaCl) 2954, 2908, 2873, 1492, 1464,1418, 1356, 1326, 1300, 1249, 1233, 1166, 1131, 1101, 1071, 1007, 958,897, 821 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₁₃H₁₉NSi [M+H]+:217.1280; measured 217.1287.

This product was also prepared by heating N-methylindole 1a (62 mg, 0.5mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv) and EtMe₂SiH (198microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 48 hoursat 23° C. After aqueous work up, the crude reaction mixture was purifiedby chromatography on silica using hexanes (isochratic) to obtain 80 mg(74%) of the title compound as a colourless oil. ¹H NMR (500 MHz,THF-d8) δ 7.48 (d, J=7.9 Hz, 1H), 7.31 (dd, J=8.4, 1.0 Hz, 1H), 7.10(ddd, J=8.2, 6.9, 1.2 Hz, 1H), 6.95 (ddd, J=7.9, 6.9, 0.9 Hz, 1H), 6.64(d, J=0.9 Hz, 1H), 3.84 (s, 3H), 1.05-0.95 (m, 3H), 0.89 (d, J=7.9 Hz,2H), 0.38 (s, 6H). ¹³C NMR (126 MHz, THF-d8) δ 140.45, 138.94, 128.58,121.45, 120.10, 118.51, 113.53, 111.90, 108.67, 32.17, 7.37, 6.77,−3.67.

Example 6.9.23: 1-Benzyl-2-(ethyldimethylsilyl)-1H-indole 2v

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-benzylindole 1b (102.5 mg, 0.5mmol, 1 equiv), EtMe₂SiH (197 μL, 1.5 mmol, 3 equiv) and 0.5 mL of THFat 45° C. for 96 h. C2:C3>20:1. The desired product 2v (87.9 mg, 60%yield) was obtained as a colorless oil after purification by silica gelflash chromatography (10% CH₂Cl₂ in hexanes). Rf=0.3 (10% CH₂Cl₂ inhexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.75-7.69 (m, 1H), 7.34-7.23 (m,3H), 7.23-7.11 (m, 3H), 6.96 (ddd, J=6.8, 2.2, 1.2 Hz, 2H), 6.88 (s,1H), 5.54 (s, 2H), 1.00 (t, J=7.9 Hz, 3H), 0.79 (q, J=7.8 Hz, 2H), 0.32(s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 140.5, 140.1, 138.4, 128.9, 128.7,127.3, 125.9, 122.4, 120.8, 119.6, 112.9, 110.1, 50.1, 7.8, 7.5, −2.6.IR (Neat Film, NaCl) 3060, 3028, 2954, 2910, 2873, 1605, 1495, 1466,1450, 1377, 1353, 1334, 1300, 1249, 1196, 1164, 1115, 1096, 1014, 958,823, 780, 725 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₁₉H₂₃NSi [M+H]+:calculated 293.1600, found 293.1590.

In a second experiment, 1-benzylindole (104 mg, 0.5 mmol, 1 equiv.),KOt-Bu (17 mg, 0.15 mmol, 0.3 equiv) and EtMe₂SiH (198 microliters, 1.5mmol, 3 equiv.) in was stirred in 1 mL of tetrahydrofuran for 65 hoursat 25° C. After aqueous work up, the crude reaction mixture was purifiedby chromatography on silica using an 80:1:4 mixture of hexanes:diethylether:triethylamine respectively to obtain 107 mg (73%) of the titlecompound as a colourless oil. ¹H NMR (500 MHz, THF-d₈) δ 7.55 (ddd,J=7.7, 1.4, 0.8 Hz, 1H), 7.22-7.16 (m, 2H), 7.16-7.09 (m, 2H), 7.02(ddd, J=8.2, 6.9, 1.4 Hz, 1H), 6.97 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 6.86(ddd, J=7.2, 1.3, 0.7 Hz, 2H), 6.78 (d, J=0.9 Hz, 1H), 5.51 (d, J=1.1Hz, 2H), 0.95-0.90 (m, 3H), 0.24 (s, 6H). ¹³C NMR (126 MHz, THF-d8) δ141.31, 140.50, 139.94, 130.09, 129.39, 127.90, 126.71, 122.96, 121.45,120.10, 113.93, 110.81, 50.62, 8.50, 7.93, −2.40.

Example 6.9.24: 1-Benzyl-2-(dimethyl(phenyl)silyl)-1H-indole 2w

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-benzylindole 1b (103.5 mg, 0.5mmol, 1 equiv), PhMe₂SiH (230 μL, 1.5 mmol, 3 equiv) and 0.5 mL of THFat 45° C. for 96 h. C2:C3>20:1. A mixture of starting material 1b andproduct 2w (174.5 mg of mixture, contains 133.9 mg of 2w, 78% yield,calculated based on ¹H NMR) was obtained after purification by silicagel flash chromatography (2% EtOAc in hexanes). Analytically purecompound 2w was obtained as a white solid after subsequent purificationby Preparative HPLC (3% EtOAc in hexanes). Rf=0.4 (5% EtOAc in hexanes);¹H NMR (500 MHz, CDCl₃) δ 7.71-7.66 (m, 1H), 7.51-7.48 (m, 2H),7.40-7.35 (m, 1H), 7.34-7.29 (m, 2H), 7.21-7.16 (m, 3H), 7.14-7.08 (m,3H), 6.90 (d, J=0.7 Hz, 1H), 6.78-6.75 (m, 2H), 5.25 (s, 2H), 0.50 (s,6H); ¹³C NMR (125 MHz, CDCl₃) δ 140.4, 139.4, 138.3, 137.5, 134.2,129.6, 128.9, 128.6, 128.1, 127.2, 125.9, 122.6, 121.0, 119.6, 114.1,110.2, 50.0, −1.7. IR (Neat Film, NaCl) 3064, 3027, 2956, 1605, 1587,1494, 1466, 1450, 1427, 1353, 1335, 1301, 1250, 1197, 1164, 1116, 1106,1096, 1014, 905, 822 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₂₃H₂₄NSi[M+H]+: 342.1673, found 342.1676.

Example 6.9.25: 1-Methyl-2-(tributylsilyl)-1H-indole 2x

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-methylindole 1a (65.6 mg, 0.5mmol, 1 equiv), n-Bu₃SiH (385 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THFat 35° C. for 65 h. C2:C3>20:1. The desired product 2x (123.5 mg, 75%yield) was obtained as a white solid after purification by silica gelflash chromatography (100% hexanes). Rf=0.5 (100% hexanes). ¹H NMR (500MHz, CDCl₃) δ 7.61 (dt, J=7.9, 1.0 Hz, 1H), 7.37-7.30 (m, 1H), 7.22(ddd, J=8.2, 6.9, 1.1 Hz, 1H), 7.08 (ddd, J=7.9, 6.9, 1.0 Hz, 1H), 6.69(d, J=0.9 Hz, 1H), 3.84 (s, 3H), 1.38-1.27 (m, 12H), 0.94-0.86 (m, 15H);¹³C NMR (125 MHz, CDCl₃) δ 140.2, 139.0, 128.6, 121.7, 120.5, 118.9,112.7, 108.9, 32.9, 26.6, 26.1, 13.6, 12.7; IR (Neat Film, NaCl) 2955,2922, 2871, 2855, 1492, 1464, 1411, 1375, 1356, 1325, 1298, 1232, 1196,1166, 1102, 1070, 897, 885, 799, 788, 749, 732 cm⁻¹; HRMS (EI+) calc'dfor C₂₁H₃₅NSi [M.+]: 329.2539, found 329.2523.

Example 6.9.26: 1-Methyl-2-(triethylsilyl)-1H-pyrrolo[3,2-b]pyridine 4a

The reaction was conducted according to the General Procedure by heatingKOt-Bu (4.5 mg, 0.04 mmol, 20 mol %), N-methyl-4-azaindole 3a (26.4 mg,0.2 mmol, 1 equiv), Et₃SiH (98 μL, 0.6 mmol, 3 equiv) and 0.2 mL of THFat 45° C. for 96 h. C2:C3=6:1. A mixture of C2- and C3-silylationproducts (16.2 mg, 33% yield) was obtained after purification by silicagel flash chromatography (50% EtOAc in hexanes). Analytically pureC2-silylation 4a was obtained as a colorless oil after subsequentpurification by Preparative TLC (50% EtOAc in hexanes). Rf=0.1 (33%EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 8.44 (dd, J=4.6, 1.4 Hz,1H), 7.60 (dt, J=8.3, 1.2 Hz, 1H), 7.09 (dd, J=8.3, 4.6 Hz, 1H), 6.90(d, J=0.9 Hz, 1H), 3.83 (s, 3H), 1.03-0.97 (m, 9H), 0.96-0.89 (m, 6H);¹³C NMR (125 MHz, CDCl₃) δ 147.0, 143.0, 142.7, 133.0, 116.4, 116.1,113.8, 33.1, 7.6, 4.0. IR (Neat Film, NaCl) 2953, 2909, 2874, 1596,1557, 1455, 1434, 1413, 1355, 1317, 1288, 1237, 1134, 1064, 1004, 800cm⁻¹; HRMS (ESI+) calc'd for C₁₄H₂₃N₂Si [M+H]+: 247.1625, found247.1621.

Example 6.9.27: 1-Methyl-2-(triethylsilyl)-1H-pyrrolo[3,2-c]pyridine 4b

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-methyl-5-azaindole 3b (66.0 mg,0.5 mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL ofTHF at 45° C. for 120 h. C2:C3>20:1. The desired product 4b (37.9 mg,31% yield) was obtained as a yellow oil after purification by silica gelflash chromatography (100% EtOAc). Rf=0.2 (100% EtOAc); ¹H NMR (500 MHz,CDCl₃) δ 8.87 (d, J=1.1 Hz, 1H), 8.28 (d, J=5.9 Hz, 1H), 7.24-7.18 (m,1H), 6.80 (d, J=0.9 Hz, 1H), 3.82 (s, 3H), 1.02-0.96 (m, 9H), 0.94-0.87(m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 143.7, 143.6, 140.8, 140.4, 125.7,112.9, 104.5, 32.9, 7.6, 4.0. IR (Neat Film, NaCl) 2953, 2909, 2874,1597, 1563, 1485, 1463, 1435, 1415, 1368, 1334, 1310, 1291, 1219, 1184,1123, 1069, 1004, 900, 809 cm⁻¹; HRMS (ESI+) calc'd for C₁₄H₂₃N₂Si[M+H]+: 247.1625, found 247.1626.

Example 6.9.28: 1-Methyl-2-(triethylsilyl)-1H-pyrrolo[2,3-c]pyridine 4c

The reaction was conducted according to the General Procedure by heatingKOt-Bu (5.8 mg, 0.52 mmol, 20 mol %), N-methyl-6-azaindole 3c (35.0 mg,0.26 mmol, 1 equiv), Et₃SiH (126 μL, 0.78 mmol, 3 equiv), and 0.3 mL ofTHF at 45° C. for 94 h. C2:C3>20:1. The desired product 4c (32.9 mg, 50%yield) was obtained as a yellow oil after purification by silica gelflash chromatography (gradient elution, 2.5→5% MeOH in CH₂Cl₂). Rf=0.3(5% MeOH in CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 8.76 (s, 1H), 8.20 (d,J=5.5 Hz, 1H), 7.47 (dd, J=5.5, 1.1 Hz, 1H), 6.68 (d, J=0.8 Hz, 1H),3.93 (s, 3H), 1.03-0.97 (m, 9H), 0.95-0.89 (m, 6H); ¹³C NMR (125 MHz,CDCl₃) δ 143.5, 138.1, 137.2, 133.0, 132.6, 114.7, 112.0, 33.3, 7.5,3.9. IR (Neat Film, NaCl) 2952, 2909, 2874, 1594, 1559, 1496, 1475,1457, 1415, 1358, 1333, 1315, 1286, 1241, 1167, 1120, 1070, 1004, 817,808 cm⁻¹; HRMS (ESI+) calc'd for C₁₄H₂₃N₂Si [M+H]+: 247.1625, found247.1620.

Example 6.9.29: 1-Methyl-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine 4d

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-methyl-7-azaindole 3d (66 mg,0.5 mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL ofTHF at 35° C. for 63 h. C2:C3>20:1. The desired product 4d (87.1 mg, 71%yield) was obtained as a colorless oil after purification by silica gelflash chromatography (gradient elution, 0→10% EtOAc in hexanes). Rf=0.3(10% EtOAc in hexanes); 1H NMR (500 MHz, CDCl₃) δ 8.33 (dd, J=4.7, 1.6Hz, 1H), 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.02 (dd, J=7.8, 4.7 Hz, 1H),6.67 (s, 1H), 3.95 (s, 3H), 1.04-0.97 (m, 9H), 0.96-0.88 (m, 6H); ¹³CNMR (125 MHz, CDCl₃) δ 151.0, 143.2, 139.2, 128.3, 120.7, 115.3, 111.0,31.4, 7.6, 3.9. IR (Neat Film, NaCl) 3052, 2953, 2910, 2874, 1590, 1570,1489, 1444, 1403, 1302, 1286, 1226, 1162, 1134, 1107, 1066, 1004, 906,804, 772, 739 cm⁻¹; HRMS (FAB+) calc'd for C₁₄H₂₃N₂Si [M+H]+: 247.1631,found 247.1637. The HSQC spectrum of this reaction product haspreviously been reported in U.S. Pat. No. 9,000,167.

Example 6.9.30: 1-Methyl-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine 4e

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-benzyl-7-azaindole 3e (104.0 mg,0.5 mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL ofTHF at 45° C. for 144 h. C2:C3>20:1. The desired product 4e (89.4 mg,56% yield) was obtained as a colorless oil purification by silica gelflash chromatography (gradient elution, 2.5→5% EtOAc in hexanes). Rf=0.3(5% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 8.34 (dd, J=4.7, 1.6Hz, 1H), 7.94 (dd, J=7.8, 1.6 Hz, 1H), 7.25-7.16 (m, 3H), 7.07 (dd,J=7.8, 4.6 Hz, 1H), 6.87-6.85 (m, 2H), 6.79 (s, 1H), 5.69 (s, 2H),0.91-0.83 (m, 9H), 0.74-0.69 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 151.2,143.7, 139.04, 138.96, 128.6, 128.4, 127.0, 125.9, 120.5, 115.7, 112.2,47.8, 7.4, 3.7. IR (Neat Film, NaCl) 2954, 2874, 1589, 1570, 1495, 1452,1439, 1422, 1378, 1357, 1309, 1239, 1157, 1103, 1004, 909, 803, 777cm⁻¹; HRMS (MM: ESIAPCI+) calc'd for C₂₀H₂₇N₂Si [M+H]+: 323.1938, found323.1947.

Example 6.9.31: 1-Benzyl-2-(diethylsilyl)-1H-pyrrolo[2,3-b]pyridine 4f

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-benzyl-7-azaindole 3e (104.5 mg,0.5 mmol, 1 equiv) and Et₂SiH₂ (194 μL, 1.5 mmol, 3 equiv) at 60° C. for84 h. C2:C3>20:1. The desired product 4f (96.2 mg, 65% yield) wasobtained as a yellow oil after purification by silica gel flashchromatography (3% EtOAc in hexanes). Rf=0.4 (10% EtOAc in hexanes); ¹HNMR (500 MHz, CDCl₃) δ 8.37 (dd, J=4.7, 1.6 Hz, 1H), 7.95 (dd, J=7.8,1.6 Hz, 1H), 7.30-7.16 (m, 3H), 7.09 (dd, J=7.8, 4.6 Hz, 1H), 7.01-6.99(m, 2H), 6.80 (s, 1H), 5.71 (s, 2H), 4.32 (p, J=3.3 Hz, 1H), 0.95 (t,J=7.9 Hz, 6H), 0.78-0.63 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ 150.9,143.8, 138.9, 137.4, 128.6, 128.5, 127.2, 126.6, 120.5, 115.8, 111.7,47.6, 8.1, 3.4. IR (Neat Film, NaCl) 2955, 2873, 2120, 1590, 1568, 1495,1453, 1439, 1422, 1358, 1300, 1235, 1156, 1100, 1009, 973, 910, 808cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₁₈H₂₃N₂Si [M+H]+: 295.1625, found295.1636.

Example 6.9.32:1-Benzyl-2-(dimethyl(phenyl)silyl)-1H-pyrrolo[2,3-b]pyridine 4g

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), N-benzyl-7-azaindole 3e (103.9 mg,0.5 mmol, 1 equiv) and PhMe₂SiH (230 μL, 1.5 mmol, 3 equiv) at 60° C.for 96 h. C2:C3>20:1. The desired product 4g (118.0 mg, 69% yield) wasobtained as a yellow oil after purification by silica gel flashchromatography (3% EtOAc in hexanes). Rf=0.4 (10% EtOAc in hexanes); ¹HNMR (500 MHz, CDCl₃) δ 8.35 (dd, J=4.7, 1.6 Hz, 1H), 7.97 (dd, J=7.8,1.6 Hz, 1H), 7.49-7.45 (m, 2H), 7.41-7.38 (m, 1H), 7.37-7.32 (m, 2H),7.20-7.13 (m, 3H), 7.08 (dd, J=7.8, 4.6 Hz, 1H), 6.84 (s, 1H), 6.77-6.68(m, 2H), 5.46 (s, 2H), 0.42 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 151.3,144.0, 140.0, 138.8, 136.9, 134.2, 129.7, 128.8, 128.5, 128.1, 127.0,126.1, 120.4, 115.9, 112.2, 47.6, −2.0. IR (Neat Film, NaCl) 3050, 3027,2956, 1589, 1569, 1495, 1439, 1427, 1359, 1309, 1250, 1156, 1107, 1029,987, 910, 822 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₂₂H₂₃N₂Si [M+H]+:343.1625, found 343.1635.

Example 6.9.33: Benzofuran-2-yltriethyl silane

The reaction was conducted according to the General Procedure by heatingbenzofuran (59 mg, 0.5 mmol, 1 equiv.), KOt-Bu (19.6 mg, 0.18 mmol, 0.35equiv.) and Et₃SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL oftetrahydrofuran for 45 hours at 60° C. After aqueous work up, the crudereaction mixture was purified by chromatography on silica eluting withhexanes (isochratic) to obtain 44 mg (38%) of the title compound as acolourless oil. ¹H NMR (500 MHz, Acetone-d6) δ 7.64 (ddd, J=7.7, 1.3,0.7 Hz, 1H), 7.53 (dd, J=8.2, 0.9 Hz, 1H), 7.30 (ddd, J=8.3, 7.2, 1.3Hz, 1H), 7.22 (ddd, J=7.7, 7.2, 1.0 Hz, 1H), 7.16 (d, J=1.0 Hz, 1H),1.09-0.98 (m, 9H), 0.92-0.84 (m, 6H). The HSQC spectrum of this reactionproduct has previously been reported in U.S. Pat. No. 9,000,167.

Example 6.9.34: Benzo[b]thiophen-2-yltriethylsilane 4h

(Note: the product of this reaction was previously mischaracterized asbenzo[b]thiophen-3-yltriethylsilane. The spectral data has beenre-interpreted to provide the structure given here). The reaction wasconducted according to the General Procedure by heating KOt-Bu (11.2 mg,0.1 mmol, 20 mol %), benzo[b]thiophene 3h (67.0 mg, 0.5 mmol, 1 equiv),Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 25° C. for 60h. The desired product 4h (120.3, 97% yield) was obtained as a colorlessoil after purification by silica gel flash chromatography (100%hexanes). Rf=0.6 (100% hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.91 (m, 1H),7.87-7.81 (m, 1H), 7.49 (m, 1H), 7.41-7.29 (m, 2H), 1.07-1.03 (m, 9H),0.96-0.85 (m, 6H). The HSQC spectrum of this reaction product haspreviously been reported in U.S. Pat. No. 9,000,167.

This material was also made at scale as follows. In a nitrogen-filledglove box, KOt-Bu (1.7 g, 15 mmol, 20 mol %), benzo[b]thiophene 3h (10.1g, 75 mmol, 1 equiv), Et₃SiH (23.3 mL, 146 mmol, 2 equiv), and 75 mL ofTHF were added to a 250 mL media jar equipped with a magnetic stir barand sealed with a polypropylene cap. The reaction mixture was stirred at25° C. for 60 h. The jar was then removed from the glovebox, openedcarefully (caution: gas released!), and diluted with anhydrous Et₂O (30mL). The reaction was filtered, the solvent was removed in vacuo and theresidual volatiles were removed under high vacuum (30 millitorr, 23°C.). The desired product 4h (17.3 g, 93% yield) was obtained as acolorless oil after purification by silica gel flash chromatography(100% hexanes).

Example 6.9.35: Benzo[b]thiophen-2-yldimethyl(phenyl)silane 4i

(Note: the product of this reaction was previously mischaracterized asbenzo[b]thiophen-3-yldimethyl(phenyl)silane. The spectral data has beenre-interpreted to provide the structure given here). The reaction wasconducted according to the General Procedure by heating KOt-Bu (11.2 mg,0.1 mmol, 20 mol %), benzo[b]thiophene 3h (67.0 mg, 0.5 mmol, 1 equiv),PhMe₂SiH (230 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 25° C. for 60h. The desired product 4i (116.6 mg, 87% yield) was obtained as acolorless oil after purification by silica gel flash chromatography(100% hexanes). Rf=0.5 (100% hexanes). ¹H NMR (500 MHz, CDCl₃) δ7.94-7.87 (m, 1H), 7.87-7.79 (m, 1H), 7.68-7.59 (m, 2H), 7.51 (d, J=0.8Hz, 1H), 7.46-7.39 (m, 3H), 7.38-7.31 (m, 2H), 0.69 (s, 6H).

¹³C NMR (126 MHz, CDCl₃) δ 144.01, 141.12, 140.18, 137.29, 134.13,132.41, 129.70, 128.09, 124.45, 124.18, 123.69, 122.33, −1.42. HRMS:[C₁₆H₁₆SSi] calculated 268.0743, measured 268.0742

Example 6.9.36: 2-(5-(Triethylsilyl)thiophen-2-yl)pyridine 4j

The reactions were conducted according to the General Procedure.Condition A: The reaction was performed with KOt-Bu (11.2 mg, 0.1 mmol,20 mol %), 2-(thiophen-2-yl)pyridine 3j (80.5 mg, 0.5 mmol, 1 equiv),Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 25° C. for 35h. The desired product 4j (129.3 mg, 94% yield) was obtained as acolorless oil after purification by silica gel flash chromatography (5%EtOAc in hexanes). Condition B: The reaction was performed with KOt-Bu(19.6 mg, 0.18 mmol, 3.5 mol %), 2-(thiophen-2-yl)pyridine 3j (0.81 g, 5mmol, 1 equiv), Et₃SiH (2.43 mL, 15 mmol, 3 equiv), and 3.0 mL of THF at25° C. for 96 h. The desired product 4j (1.13 g, 82% yield) was obtainedas a colorless oil after purification by silica gel flash chromatography(5% EtOAc in hexanes). Rf=0.3 (5% EtOAc in hexanes); ¹H NMR (500 MHz,CDCl₃) δ 8.56 (d, J=4.7 Hz, 1H), 7.61 (dt, J=3.9, 1.7 Hz, 3H), 7.23 (d,J=3.3 Hz, 1H), 7.08 (q, J=4.8 Hz, 1H), 1.01 (t, J=7.9 Hz, 9H), 0.82 (q,J=7.9 Hz, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 152.8, 149.8, 149.6, 139.7,136.6, 135.6, 125.7, 121.8, 119.0, 7.4, 4.5; IR (Neat Film, NaCl) 3054,3001, 2953, 2909, 2874, 1585, 1563, 1528, 1517, 1464, 1436, 1422, 1377,1315, 1290, 1238, 1207, 1151, 1077, 1066, 1047, 1007, 990, 962, 807,774, 737 cm⁻¹; HRMS (FAB+) calc'd for C₁₅H₂₂NSSi [M+H]+: 276.1242, found276.1239.

Example 6.9.37: 2-(5-(Ethyldimethylsilyl)thiophen-2-yl)pyridine 4k

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 2-(thiophen-2-yl)pyridine 3j (80.5mg, 0.5 mmol, 1 equiv), EtMe₂SiH (198 μL, 1.5 mmol, 3 equiv), and 0.5 mLof THF at 35° C. for 48 h. The desired product 4k (107.4 mg, 87% yield)was obtained as a colorless oil after purification by silica gel flashchromatography (10% Et₂O in hexanes). Rf=0.4 (10% Et₂O in hexanes); ¹HNMR (500 MHz, CDCl₃) δ 8.58 (ddd, J=4.9, 1.8, 1.1 Hz, 1H), 7.72-7.63 (m,2H), 7.62 (d, J=3.5 Hz, 1H), 7.24 (d, J=3.5 Hz, 1H), 7.13 (ddd, J=6.7,4.9, 2.0 Hz, 1H), 1.05-0.96 (m, 3H), 0.78 (qd, J=7.8, 0.8 Hz, 2H), 0.32(s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 152.7, 149.7, 149.6, 141.9, 136.6,135.0, 125.6, 121.7, 118.9, 8.3, 7.2, −2.5; IR (Neat Film, NaCl) 3054,3001, 2953, 2909, 2874, 1585, 1563, 1528, 1517, 1464, 1436, 1422, 1315,1290, 1248, 1207, 1151, 1077, 1066, 1047, 1007, 990, 964, 836, 812, 774,752, 737, 712 cm⁻¹; HRMS (FAB+) calc'd for C₁₃H₁₈NSSi [(M+H)+−H2]:248.0929, found 248.0935.

Example 6.9.38: 2-(5-(Dimethyl(phenyl)silyl)thiophen-2-yl)pyridine 4l

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 2-(thiophen-2-yl)pyridine 3j (80.5mg, 0.5 mmol, 1 equiv), PhMe₂SiH (230 μL, 1.5 mmol, 3 equiv), and 1.0 mLof THF at 35° C. for 48 h. The desired product 4l (118.1 mg, 80% yield)was obtained as a colorless oil after purification by silica gel flashchromatography (10% Et₂O in hexanes). Rf=0.3 (10% Et2O in hexanes); ¹HNMR (500 MHz, CDCl₃) δ 8.60-8.54 (m, 1H), 7.72-7.56 (m, 5H), 7.43-7.33(m, 3H), 7.26 (m, 1H), 7.14 (m, 1H), 0.63 (s, 6H); ¹³C NMR (125 MHz,CDCl₃) δ 152.4, 150.3, 149.5, 140.6, 137.3, 136.6, 136.0, 133.8, 129.3,127.8, 125.6, 121.8, 118.9, −1.6; IR (Neat Film, NaCl) 3067, 2955, 1586,1563, 1527, 1463, 1423, 1316, 1290, 1249, 1207, 1151, 1112, 1077, 1005,989, 963, 807, 773, 731 cm⁻¹; HRMS (FAB+) calc'd for C₁₇H₁₈NSSi [M+H]+:296.0929, found 296.0938.

Example 6.9.39: Triethyl(5-pentylthiophen-2-yl)silane 4m

The reaction was conducted according to the General Procedure. ConditionA: The reaction was performed with KOt-Bu (11.2 mg, 0.1 mmol, 20 mol %),2-pentylthiophene 3m (77.0 mg, 0.5 mmol, 1 equiv), Et₃SiH (243 μL, 1.5mmol, 3 equiv), and 0.5 mL of THF at 25° C. for 48 h. The desiredproduct 4m (130.0 mg, 96% yield) was obtained as a colorless oil afterpurification by silica gel flash chromatography (100% hexanes).Condition B: The reaction was performed with KOt-Bu (5.6 mg, 0.05 mmol,1 mol %), 2-pentylthiophene 3m (770.4 mg, 5.0 mmol, 1 equiv), Et₃SiH(2.43 mL, 15 mmol, 3 equiv), and 3.0 mL of THF at 25° C. for 96 h. Thedesired product 4m (1.23 g, 92% yield) was obtained as a colorless oilafter purification by silica gel flash chromatography (100% hexanes).Rf=0.6 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.12 (dd, J=3.3, 1.5Hz, 1H), 6.91 (dt, J=3.3, 1.0 Hz, 1H), 2.90 (td, J=7.7, 1.2 Hz, 2H),1.81-1.71 (m, 2H), 1.48-1.36 (m, 4H), 1.06 (t, J=7.8 Hz, 9H), 0.99-0.94(m, 3H), 0.84 (qd, J=7.8, 1.0 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 151.6,134.7, 134.1, 125.5, 31.7, 31.6, 30.2, 22.6, 14.1, 7.5, 4.7; IR (NeatFilm, NaCl) 3054, 2955, 2934, 2874, 1750, 1528, 1456, 1438, 1413, 1378,1339, 1235, 1213, 1058, 1011, 988, 799, 736 cm⁻¹; HRMS (FAB+) calc'd forC₁₅H₂₇SSi [(M+H)−H2]+: 267.1603, found 267.1609.

Example 6.9.40: Triethyl(5-pentylfuran-2-yl)silane 4n

The reaction was conducted according to the General Procedure by heatingKOt-Bu (8.4 mg, 0.075 mmol, 1.5 mol %), 2-pentylfuran 3n (691 mg, 5.0mmol, 1 equiv), Et₃SiH (2.43 mL, 15 mmol, 3 equiv), and 3 mL of THF at25° C. for 96 h. The desired product 4n (1.15 g, 91% yield) was obtainedas a colorless oil after purification by silica gel flash chromatography(100% hexanes). Rf=0.6 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ 6.53(d, J=3.0 Hz, 1H), 5.96 (dt, J=3.0, 0.9 Hz, 1H), 2.67-2.60 (m, 2H), 1.64(dq, J=9.4, 7.4 Hz, 2H), 1.36-1.28 (m, 4H), 1.05-0.95 (m, 9H), 0.92-0.85(m, 3H), 0.74 (qd, J=7.8, 0.8 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 161.2,156.2, 121.5, 104.6, 31.6, 28.3, 27.9, 22.6, 14.1, 7.5, 3.6; IR (NeatFilm, NaCl) 3108, 2954, 2933, 2874, 1807, 1721, 1588, 1493, 1459, 1414,1378, 1340, 1237, 1186, 1173, 1118, 1084, 1011, 962, 923, 782, 736, 724cm⁻¹; HRMS (FAB+) calc'd for C₁₅H₂₇OSi [(M+H)−H2]+: 251.1831, found251.1821.

This material was also made at scale using the same procedure as for themultigram scale synthesis of 4h. The reaction was performed with KOt-Bu(1.6 g, 14.6 mmol, 20 mol %), 2-pentylfuran 3n (10.1 g, 73 mmol, 1equiv), Et₃SiH (23.3 mL, 146 mmol, 2 equiv), and 73 mL of THF at 25° C.for 72 h. The desired product 4n (17.4 g, 95% yield) was obtained as acolorless oil after filtration, removal of volatiles under high vacuum(30 millitorr, 23° C.) and purification by silica gel flashchromatography (100% hexanes).

Example 6.9.41: Reaction of 2-pentylfuran 3n with Et₂SiH₂

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 2-pentylfuran 3n (69.1 mg, 0.5mmol, 1 equiv), Et₂SiH₂ (195 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THFat 25° C. for 76 h. The desired product 4o (87.4 mg, 78% yield) andsilicon-tethered product SI-4o (12.4 mg, 8% yield) were obtained afterpurification by silica gel flash chromatography (100% hexanes).

Diethyl(5-pentylfuran-2-yl)silane 4o

Colorless oil, Rf=0.6 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ 6.63 (d,J=3.1 Hz, 1H), 6.00 (dt, J=3.1, 0.9 Hz, 1H), 4.21 (p, J=3.2 Hz, 1H),2.75-2.64 (m, 2H), 1.73-1.62 (m, 2H), 1.38-1.32 (m, 4H), 1.11-1.04 (m,6H), 0.95-0.90 (m, 3H), 0.88-0.81 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ161.8, 153.7, 122.7, 105.0, 31.6, 28.4, 27.9, 22.6, 14.1, 8.1, 3.2; IR(Neat Film, NaCl) 2955, 2931, 2873, 2120, 1588, 1493, 1461, 1233, 1082,1010, 974, 925, 798, 715 cm⁻¹; HRMS (FAB+) calc'd for C₁₃H₂₃OSi[(M+H)−H2]+: 223.1518, found 223.1519.

Diethylbis(5-pentylfuran-2-yl)silane SI-4o

Colorless oil, Rf=0.7 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ 6.62 (d,J=3.1 Hz, 2H), 5.98 (dt, J=3.1, 0.9 Hz, 2H), 2.69-2.61 (m, 4H),1.70-1.59 (m, 4H), 1.36-1.30 (m, 8H), 1.08-1.01 (m, 6H), 1.01-0.93 (m,4H), 0.93-0.81 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 161.5, 153.7, 122.8,104.8, 31.4, 28.2, 27.7, 22.4, 13.9, 7.2, 4.2; IR (Neat Film, NaCl)2955, 2928, 2873, 2859, 1587, 1493, 1461, 1378, 1233, 1187, 1122, 1010,961, 925, 783, 726 cm⁻¹; HRMS (EI+) calc'd for C₂₂H₃₆O₂Si [M.+]:360.2485, found 360.2468.

Example 6.9.42: Tributyl(5-pentylfuran-2-yl)silane 4p

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 2-pentylfuran 3n (69.1 mg, 0.5mmol, 1 equiv), n-Bu₃SiH (386 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THFat 25° C. for 108 h. The desired product 4p (137.8 mg, 82% yield) wasobtained as a colorless oil after purification by silica gel flashchromatography (100% hexanes). Rf=0.71 (100% hexanes); ¹H NMR (500 MHz,CDCl₃) δ 6.50 (d, J=3.0 Hz, 1H), 5.95 (d, J=3.0, 1H), 2.67-2.60 (m, 2H),1.69-1.59 (m, 2H), 1.39-1.24 (m, 16H), 0.94-0.83 (m, 12H), 0.79-0.69 (m,6H); ¹³C NMR (125 MHz, CDCl₃) δ 161.0, 156.8, 121.3, 104.7, 31.6, 28.3,28.0, 26.7, 26.2, 22.6, 14.1, 13.9, 12.3; IR (Neat Film, NaCl) 3107,2956, 2923, 2871, 2857, 2099, 1677, 1588, 1493, 1464, 1410, 1376, 1341,1296, 1271, 1217, 1187, 1175, 1082, 1050, 1010, 961, 925, 885, 781, 759,732 cm⁻¹; HRMS (EI+) calc'd for C₂₁H₄₀OSi [M.+]: 336.2848, found336.2859.

Example 6.9.43: 2,5-Bis(triethylsilyl)thiophene 4q

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), thiophene 3q (42.1 mg, 0.5 mmol, 1equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 25° C.for 72 h. The desired product 4q (134.2 mg, 86% yield) was obtained as acolorless oil after purification by silica gel flash chromatography(100% hexanes). Rf=0.6 (100% hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.40(s, 2H), 1.02-0.99 (m, 18H), 0.83-0.79 (m, 12H).

Example 6.9.44: Reaction of 1-benzyl-1H-pyrrole 3s with Et₃SiH

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 1-benzyl-1H-pyrrole 3s (78.5 mg,0.5 mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL ofTHF at 25° C. for 108 h. The desired product 4s (100.3 mg, 74% yield)and bis-silylation product SI-4s (9.6 mg, 5%) were obtained afterpurification by silica gel flash chromatography (100% hexanes).

1-Benzyl-2-(triethylsilyl)-1H-pyrrole 4s

Colorless oil, Rf=0.3 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.40-7.32 (m, 2H), 7.32-7.25 (m, 1H), 7.04-6.98 (m, 2H), 6.86 (dd,J=2.4, 1.5 Hz, 1H), 6.51 (dd, J=3.5, 1.5 Hz, 1H), 6.30 (dd, J=3.4, 2.4Hz, 1H), 5.22 (s, 2H), 0.95 (t, J=7.8 Hz, 9H), 0.73 (q, J=7.8 Hz, 6H);¹³C NMR (125 MHz, CDCl₃) δ 139.2, 129.9, 128.7, 127.5, 126.62, 126.56,120.9, 108.9, 53.5, 7.6, 4.2; IR (Neat Film, NaCl) 3088, 3064, 3029,2952, 2908, 2873, 1516, 1506, 1495, 1454, 1418, 1353, 1329, 1288, 1237,1175, 1112, 1080, 1008, 969, 760 cm⁻¹; HRMS (EI+) calc'd for C₁₇H₂₅NSi[M.+]: 271.1756, found 271.1755.

1-Benzyl-2,5-bis(triethylsilyl)-1H-pyrrole SI-4s

Colorless oil, Rf=0.4 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.29-7.21 (m, 2H), 7.21-7.15 (m, 1H), 6.72 (dq, J=7.1, 1.0 Hz, 2H), 6.52(s, 2H), 5.28 (s, 2H), 0.85-0.82 (m, 18H), 0.63-0.52 (m, 12H); ¹³C NMR(125 MHz, CDCl₃) δ 140.4, 135.6, 128.2, 126.9, 125.5, 121.2, 53.3, 7.4,3.9; IR (Neat Film, NaCl) 3027, 2952, 2909, 2874, 1605, 1498, 1485,1454, 1416, 1377, 1343, 1277, 1237, 1161, 1075, 1002, 912, 775, 764, 731cm⁻¹; HRMS (EI+) calc'd for C₂₃H₃₉NSi₂ [M.+]: 385.2621, found 385.2638.

Example 6.9.45: 1-Methyl-5-(triethylsilyl)-1H-pyrazole 4t

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 1-methyl-1H-pyrazole 3t (41.1 mg,0.5 mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL ofTHF at 25° C. for 120 h. The desired product 4t (72.6 mg, 74% yield) wasobtained as a colorless oil after purification by silica gel flashchromatography (1:1 Et2O:hexanes). Rf=0.3 (1:1 Et2O:hexanes).(Despotopoulou, C.; et al., P Org. Lett. 2009, 11, 3326) ¹H NMR (500MHz, CDCl₃) δ 7.47 (d, J=1.9 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 3.95 (s,3H), 0.96 (m, 9H), 0.83 (m, 6H).

Example 6.9.46: Dibenzo[b,d]thiophen-4-yltriethylsilane 4u

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), dibenzothiophene 3u (92 mg, 0.5mmol, 1.0 equiv), Et₃SiH (243 μL, 1.5 mmol, 3.0 equiv), and 3 mL ofdioxane at 85° C. for 72 h. The desired product 4u (55.4 mg, 38% yield)was obtained as a colorless oil after purification by silica gel flashchromatography (100% hexanes). Rf=0.7 (100% hexanes); ¹H NMR (500 MHz,CDCl₃) δ 8.17 (m, 2H), 7.86 (m, 1H), 7.58 (m, 1H), 7.45 (m, 3H),1.10-0.93 (m, 15H); ¹³C NMR (125 MHz, CDCl₃) δ 145.6, 139.3, 135.4,134.7, 133.7, 131.5, 126.5, 124.2, 123.7, 122.4, 122.2, 121.4, 7.4, 3.2.IR (Neat Film, NaCl) 3060, 2953, 2908, 2873, 1450, 1440, 1415, 1366,1283, 1250, 1238, 1098, 1080, 1042, 1019, 1003, 972, 812, 749, 733 cm⁻¹;HRMS (EI+) calc'd for C₁₈H₂₂SSi [M.+]: 298.1212, found 298.1214. TheHSQC spectrum of this reaction product has previously been reported inU.S. Pat. No. 9,000,167.

Example 6.9.47: Reaction of dibenzo[b,d]furan 3v with Et₃SiH

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), dibenzo[b,d]furan 3v (84.1 mg, 0.5mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at65° C. for 65 h. Desired product 4v (100.2 mg, 71% yield) andbis-silylated product SI-4v (6.9 mg, 4% yield) were obtained afterpurification by silica gel flash chromatography (100% hexanes).

Dibenzo[b,d]furan-4-yltriethylsilane 4v

Colourless oil, Rf=0.6 (100% hexanes). ¹H NMR (500 MHz, CDCl₃) δ8.01-7.94 (m, 2H), 7.61-7.50 (m, 2H), 7.46 (td, J=7.7, 1.4 Hz, 1H), 7.34(td, J=7.6, 4.4 Hz, 2H), 1.02 (m, 15H).

4,6-Bis(triethylsilyl)dibenzo[b,d]furan SI-4v

White solid, Rf=0.7 (100% hexanes). ¹H NMR (500 MHz, CDCl₃) δ 7.99 (dd,J=7.6, 1.4 Hz, 2H), 7.54 (dd, J=7.1, 1.4 Hz, 2H), 7.35 (t, J=7.4 Hz,2H), 1.12-0.96 (m, 30H).

Example 6.9.48: Triethyl(6-methoxydibenzo[b,d]furan-4-yl)silane 4w

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 4-methoxydibenzo[b,d]furan 3w(99.0 mg, 0.5 mmol, 1 equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and0.5 mL of THF at 65° C. for 65 h. The desired product 4w (99.9 mg, 64%yield) was obtained as a colorless oil after purification by silica gelflash chromatography (100% hexanes). Rf=0.3 (100% hexanes); ¹H NMR (500MHz, CDCl₃) δ 7.94 (dd, J=7.6, 1.4 Hz, 1H), 7.53 (ddd, J=15.4, 7.4, 1.2Hz, 2H), 7.37-7.30 (m, 1H), 7.24 (t, J=7.8 Hz, 1H), 6.99 (dd, J=8.0, 1.0Hz, 1H), 4.09 (s, 3H), 1.08-0.95 (m, 15H); ¹³C NMR (125 MHz, CDCl₃) δ161.1, 145.7, 145.3, 133.4, 126.1, 123.0, 122.8, 122.3, 121.5, 120.4,112.9, 111.0, 56.9, 7.4, 3.5; IR (Neat Film, NaCl) 3052, 2952, 2925,2873, 2852, 2361, 1627, 1596, 1576, 1497, 1483, 1456, 1432, 1387, 1322,1308, 1270, 1220, 1180, 1168, 1147, 1125, 1038, 1006, 854, 836, 767,752, 729 cm⁻¹; HRMS (EI+) calc'd for C₁₉H₂₄O₂Si [M.+]: 312.1546, found312.1555.

Example 6.9.49: Silylation of pyridine

The reaction was conducted according to the General Procedure by heatingpyridine (40 mg, 0.5 mmol, 1 equiv.), KOt-Bu (17 mg, 0.15 mmol, 0.3equiv) and Et₃SiH (240 microliters, 1.5 mmol, 3 equiv.) in 1 mL oftetrahydrofuran for 65 hours at 65° C. After aqueous work up, the crudereaction mixture was purified by chromatography on silica using an80:1:4 mixture of hexanes:diethyl ether:triethylamine respectively toobtain 14 mg (15%) of the title compound as a colourless oily solid. ¹HNMR (500 MHz, THF-d₈) δ 8.99-8.16 (m, 2H), 7.62-7.07 (m, 2H), 1.01-0.93(m, 6H), 0.91-0.79 (m, 4H). ¹³C NMR (126 MHz, THF-d₈) δ 149.88, 129.76,129.29, 7.70, 3.66. HRMS: [C₁₁H₂₀NSi] calculated 194.1365, measured194.1367.

Attempts to reproduce this experiment resulted in variable yields forpyridine, typically yielding less than about 5% of the indicatedproduct. Experiments with other electron-deficient heteroarenes, such asquinoline, isoquinoline, and acridine, under comparable conditions,likewise resulted either low yields (<5%) or no reaction.

Example 6.9.50: Attempted silylation of 4-methoxypyridine

The reaction was conducted according to the General Procedure by heating4-methoxypyridine (55 mg, 0.5 mmol, 1 equiv.), KOt-Bu (17 mg, 0.15 mmol,0.3 equiv) and Et₃SiH (240 microliters, 1.5 mmol, 3 equiv.) in 1 mL oftetrahydrofuran for 65 hours at 65° C. The reaction was diluted withdiethyl ether (1 mL), quenched with water (0.5 mL) and the organic phasewas analyzed by GC-MS, GC-FID and ¹H NMR analysis and revealed noapparent conversion of the starting material to silylated products.

Example 6.9.51: Attempted silylation of 2,6 dimethoxypyridine

The reaction was conducted according to the General Procedure by heating2,6-dimethoxypyridine (70 mg, 0.5 mmol, 1 equiv.), KOt-Bu (17 mg, 0.15mmol, 0.3 equiv) and Et₃SiH (240 microliters, 1.5 mmol, 3 equiv.) in 1mL of tetrahydrofuran for 65 hours at 65° C. The reaction was dilutedwith diethyl ether (1 mL), quenched with water (0.5 mL) and the organicphase was analyzed by GC-MS, GC-FID and ¹H NMR analysis. GC-MS analysisrevealed major mass peaks corresponding to the formation of 2 silylatedproduct isomers as well as several unidentified products.

Example 7: Expanded Reactions Scenarios—Sensitivities of Substrates andFunctional Group Tolerances

The general and expansive utility of the present methods are alreadydescribed herein, but for the sake of completeness, additional specificexamples and reaction schemes are provided here. Also included are newmethodologies for preparing and characterizing these materials.

As an expansion to the earlier examples, a variety of indoles with Me,ethyl (Et), benzyl (Bn), phenyl (Ph) and the readily cleavablemethoxylmethyl and 2-[(trimethylsilyl)ethoxy]methyl groups on nitrogenwere evaluated and all led to regioselective C2 silylation in moderateto good yields (FIG. 2, compounds 2a-2f). Testing the influence ofsubstituents at various positions of the indole nucleus showed that Me,OMe, OBn, CH₂OMe and Ph are all compatible, giving the desired products2g-2n in 48%-83% yield. Several hydrosilanes were examined and thesilylation products (2o-2x) were obtained in good yield. A diverse rangeof N-, O- and S-containing heteroaromatics (FIG. 3), includingpyridine-containing scaffolds (4a-4g and 4j-4l), underwent the reactionwith high regioselectivity. Reactions at decreased catalyst loadings(1-3.5 mol %; 4j, 4m and 4n) and on a large scale (4h and 4n)demonstrated the robustness and preparative scale utility of theprocess. The reaction scaled to greater than 100 g without loss ofcatalyst activity under procedurally convenient conditions (FIG. 4A). Ingeneral, the reaction proved to be selective for electron-neutral andelectron-rich heterocycles; indoles possessing electron-withdrawinggroups appeared to be unreactive.

Example 7.1: Competition Experiments with Thiophene, Furan and Pyrrole

To investigate the relative reactivities of nitrogen-, oxygen-, andsulfur-containing aromatic heterocycles by KOt-Bu-catalyzed C—Hsilylation, two internal competition experiments were conducted usingone equivalent of Et₃SiH and one equivalent of each heteroarene (Scheme1). Reactions were run to partial consumption of Et₃SiH and relativequantities of silylated heteroarene were determined by ¹H NMR analysis.Results demonstrated that for 5-membered heteroarenes, the relative rateof reactivity trends as: thiophene 3q>furan 3r>1-methylpyrrole 3x.

This trend was corroborated in the competition between substitutedthiophene 3m and furan 3n. Procedures for competition experimentscomprised:

For Reaction (a):

In a nitrogen-filled glove box, KOt-Bu (11.2 mg, 0.1 mmol, 20 mol %),thiophene 3q (42.1 mg, 0.5 mmol, 1 equiv), furan 3r (34.0 mg, 0.5 mmol,1 equiv) and 1-methylpyrrole 3x (40.5 mg, 0.5 mmol, 1 equiv) were addedto a 2 dram scintillation vial equipped with a magnetic stirring bar.THF (0.3 mL) and Et₃SiH (81 μL, 0.5 mmol, 1 equiv—filtered through ashort pad of activated alumina before use) were then added. The vial wassealed and stirred at 23° C. for approximately 8 hours. The vial wasremoved from the glove box, diluted with diethyl ether (2 mL) andconcentrated under reduced pressure. Analysis of the crude reactionmixture by ¹H NMR revealed that the ratio of SI-4q:SI-4r:4x was 5:1:0.

For Reaction (b):

In a nitrogen-filled glove box, KOt-Bu (11.2 mg, 0.1 mmol, 20 mol %),2-pentylthiophene 3m (77.0 mg, 0.5 mmol, 1 equiv), and 2-pentylfuran 3n(69.1 mg, 0.5 mmol, 1 equiv) were added to a 2 dram scintillation vialequipped with a magnetic stirring bar. THF (0.3 mL) and Et₃SiH (81 μL,0.5 mmol, 1 equiv—filtered through a short pad of activated aluminabefore use) were then added. The vial was sealed and stirred at 23° C.for approximately 8 hours. The vial was removed from the glove box,diluted with diethyl ether (2 mL) and concentrated under reducedpressure. Analysis of the crude reaction mixture by ¹H NMR revealed thatthe ratio of 4m:4n was 5:1.

Example 7.2: Evaluation of Functional Group Compatibilities

In order to provide a comprehensive treatment of functional grouptolerance for the silylation reaction, a “robustness screen” as per themethod of Glorius was performed (Table 5, which follows). Certaingeneralizations can be made from the results. For example, carbonylgroups shut down the reaction (entries 16, 17). Nevertheless, protectionas an acetal, such as benzaldehyde dimethyl acetal is well tolerated(entry 18). Aryl-X groups where X═Br, I, CN, NO₂ likewise thwart thereactivity (entries 7, 8, 19 and 20). Intriguingly, these functionalgroups remain intact in most cases. However, alkene, alkyne, Ar—F,Ar—Cl, Ar—CF₃, tertiary amine, pyridine, and phosphine moieties arecompatible (entries 2-6, 9, 11, 23-26). No obvious hydrosilylation orreduction of alkene and alkyne occurs. Even free OH and NH groups aretolerated to some extent presumably due to a fortuitous silylativeprotection of the heteroatom in situ, which was confirmed by usingBnOTES as an additive (entries 12, 13, and 15). Moreover, epoxide andaziridine are tolerated as well and nucleophilic ring opening of theseadditives was not observed (entries 21, 22).

TABLE 5

4h 3h additive additive yield remaining remaining entry (1.0 equiv) (%)(%) (%) 1^(b) — 99 0 — 2

95 0 95 3

67 31 97 4

83 26 99 5 PhF 95 5 N.D.^(c) 6 PhCl 74 25 100 7 PhBr 0 89 100 8 PhI 0 9186 9 PhCF₃ 90 10 N.D.^(c) 10 PhNMe₂ 80 20 79 11 n-Bu₃N 38 55 100 12

19 73 N.D.^(c,d) 13 BnOH 31 60 0^(e) 14 PhOH 0 63 91 15 BnOTES 60 37 8916

0 83 91 17 PhCO₂Me 0 87 84 18

82 0 50^(f) 19 PhNO₂ 0 86 98 20 PhCN 0 85 81 21

60 35 100 22

40 53 100 23

71 28 N.D.^(c) 24

47 50 100 25

0 92 99 26 PPh₃ 48 50 97 ^(a) The reaction was performed with 0.5 mmolof 3h and 0.5 mmol of additive under the general procedure. 0.5 mmol oftridecane was added as an internal standard at the start of thereaction. Yield of product, remaining amounts of 3h and additive weredetermined by GC-FID analyses. ^(b)Control reaction without the additionof additive. ^(c)Not determined (overlapped with solvent peak due to thelow boiling point). ^(d)Triethyl silyl protected morpholine was formedand confirmed by GCMS analysis. ^(e)BnOTES was formed. ^(f)Acetalpartially hydrolyzed to PhCHO.

Example 8: Transformations of the Prepared Silanes Example 8.1: One-PotSi-Directed ipso-Substitution/Suzuki-Miyaura Cross-Coupling

A solution of BCl₃ (1.0 M, 0.48 mL, 0.48 mmol) in CH₂Cl₂ was added bysyringe under N₂ to a stirred solution of indolesilane 2a (98.2 mg, 0.4mmol) in CH₂Cl₂ (4 mL) at 0° C. The mixture was stirred at roomtemperature for 3 h, after which time the solvent was removed in vacuo.After the residue was dried under high vacuum for 20 min, 4-iodoanisole(94.0 mg, 0.4 mmol), Pd(PPh₃)₄ (23.2 mg, 5 mol %), DME (4 mL, degassed)and 2M Na₂CO₃ aqueous solution (1 mL, degassed) were added and themixture was stirred under reflux for 5 h. Then the reaction mixture wascooled to room temperature and water (20 mL) was added. The mixture wasextracted with Et₂O (3×30 mL), the combined organic extracts were washedwith brine, dried over Na₂SO₄ and concentrated. The desired2-(4-methoxyphenyl)-1-methyl-1H-indole 5 (71.9 mg, 76% yield) wasobtained as a white solid after purification by silica gel flashchromatography (gradient elution, 10→33% CH₂Cl₂ in hexanes). Rf=0.4 (10%EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.63 (d, J=7.7 Hz, 1H),7.49-7.39 (m, 2H), 7.36 (d, J=8.2 Hz, 1H), 7.24 (dt, J=8.2, 1.2 Hz, 1H),7.14 (dt, J=7.9, 1.0 Hz, 1H), 7.05-6.96 (m, 2H), 6.51 (br s, 1H), 3.88(s, 3H), 3.73 (s, 3H).

Example 8.2: Synthesis of a Heteroarylsilanol and Application inDenmark-Hiyama Crosscoupling

Compound 2o (44.5 mg, 0.2 mmol) and [RuCl₂(p-cymene)]2 (6.3 mg, 0.01mmol) were added to a 5 mL flask equipped with a stirring bar. The flaskwas sealed with a septum and placed under high vacuum for 5 min beforebeing connected with an O₂ balloon and back-filled with O₂, thenacetonitrile (1 mL) and H₂O (7.4 μL, 0.4 mmol) were added by syringethrough the septum. The reaction mixture was stirred for 12 h at roomtemperature. The solvent was evaporated and the product 6 (36.0 mg, 77%yield) was obtained as a colorless oil after purification by silica gelflash chromatography (gradient elution, 10→20% EtOAc in hexanes). Rf=0.2(10% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.66 (dt, J=7.9, 1.0Hz, 1H), 7.37 (dd, J=8.3, 1.0 Hz, 1H), 7.28 (ddd, J=8.3, 6.9, 1.2 Hz,1H), 7.13 (ddd, J=7.9, 6.9, 1.0 Hz, 1H), 6.80 (d, J=0.9 Hz, 1H), 3.93(s, 3H), 2.12 (br s, 1H), 1.12-1.05 (m, 6H), 1.02-0.95 (m, 4H); ¹³C NMR(125 MHz, CDCl₃) δ 140.4, 138.1, 128.4, 122.6, 121.1, 119.4, 112.7,109.4, 33.1, 7.1, 6.7. IR (Neat Film, NaCl) 3315, 2956, 2876, 1493,1463, 1413, 1357, 1328, 1300, 1234, 1166, 1102, 1075, 1007, 960, 897,839, 798, 751, 732 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₁₃H₂₀NOSi[M+H]+: 234.1309, found 234.1305.

Example 8.3: 2-(4-Methoxyphenyl)-1-methyl-1H-indole 5

In a nitrogen-filled glovebox, a 2 dram vial equipped with a stir barwas charged with NaOt-Bu (26.8 mg, 0.28 mmol) and CuI (26.6 mg, 0.14mmol), 4-iodoanisole (33.0 mg, 0.14 mmol), Pd(dba)₂ (8.2 mg, 0.014 mmol,10 mol %) and 0.2 mL of toluene. The mixture was sealed with a cap andstirred for 10 min. Then this mixture was transferred by syringe toanother 2 dram vial containing silanol 6 (33.1 mg, 0.14 mmol). The vialwas washed with toluene (2×0.4 mL) and that rinse was added to thereaction mixture. After the reaction was stirred at 30° C. for 4 h, thestarting material was completely converted (monitored by TLC). Thedesired product 5 (28.1 mg, 84% yield) was obtained as a white solidafter purification by silica gel flash chromatography (gradient elution,10→50% CH₂Cl₂ in hexanes).

Example 8.4: Direct C₇ Lithiation-Borylation by a Si-Blocking GroupStrategy

This general transformation (i.e., the protection/deprotection of the C₂position in benzofurans, indoles, and thiophenes, including the C₇lithiation-borylation of these silylated derivatives) is consideredwithin the scope of the present invention.

Example 8.4.1:Triethyl(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)silane7

To a flame-dried, round bottom flask charged with a stir bar, cappedwith a septum and under a steady stream of argon was addedbenzo[b]thiophen-2-yltriethylsilane 4h (992 mg, 4.0 mmol, 1 equiv),pentane (5.0 mL) and TMEDA (0.703 g, 0.907 mL, 1.5 equiv) at 23° C.n-Butyllithium (1.6 M in hexanes, 3.78 mL, 1.5 equiv) was added dropwisesuch that the internal temperature remained between 22 and 25° C. (athermocouple was inserted through the septum directly into the solutionfor internal monitoring of the temperature). The resultant dark brownsolution was allowed to stir at 22° C. for 20 h. The solution was thencooled to −78° C. (dry ice/acetone) and i-PrOBPin (1.52 g, 1.64 mL, 8.06mmol, 2.0 equiv) was added as a 1 M solution in THF (8.06 mL) dropwisesuch that the temperature was kept below −75° C. (careful temperaturecontrol is crucial for reproducibility). The resulting solution wasallowed to stir for 1 h at −78° C. after which time the cooling bath wasremoved. The solution was allowed to naturally warm to 23° C. andstirred at that temperature for an additional hour. The resulting turbidyellow reaction mixture was carefully quenched with NH₄Cl (5 mL). Themixture was extracted with Et₂O (3×10 mL), the combined organicfractions were washed with brine, dried over MgSO₄, filtered, and thesolvent was evaporated to give a viscous brown liquid. The desiredproduct 7 (926 mg, 64% yield) was obtained as a colorless solid afterpurification by silica gel flash chromatography (gradient elution 0→3%EtOAc in hexanes). Rf=0.2 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.91(dd, J=8.0, 1.3 Hz, 1H), 7.80 (dd, J=7.0, 1.3 Hz, 1H), 7.48 (s, 1H),7.35 (dd, J=7.9, 7.0 Hz, 1H), 1.42 (s, 12H), 1.10-1.00 (m, 9H), 0.89 (m,6H); ¹³C NMR (125 MHz, CDCl₃) δ 149.7, 140.8, 139.8, 132.0, 131.4,126.4, 123.4, 84.3, 25.1, 7.6, 4.4. IR (Neat Film, NaCl) 2955, 2937,1375, 1367, 1359, 1134, 1059, 854, 735 cm⁻¹; HRMS (EI+) calc'd forC₂₀H₃₁BSSiO₂ [M.+]: 374.1907, found 374.1907.

Example 8.4.2:2-(Benzo[b]thiophen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 8

To a vial charged with a magnetic stirbar andtriethyl(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)silane7 (300 mg, 0.80 mmol) was added CH₂Cl₂ (0.3 mL) and trifluoroacetic acid(306 μL, 4.0 mmol, 5.0 equiv) at room temperature. The reaction wasallowed to stir for 3 hours, after which time the mixture was quenchedwith water (0.5 mL), extracted with Et₂O (3×5 mL) and the combinedorganic fractions were washed with brine (5 mL). The solvents wereremoved to give 8 (203.8 mg, 98%) as a white solid without furtherpurification. Rf=0.4 (3% EtOAc in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.92 (dd, J=7.9, 1.3 Hz, 1H), 7.83 (dd, J=7.1, 1.3 Hz, 1H), 7.48 (d,J=5.5 Hz, 1H), 7.38 (dd, J=7.9, 7.0 Hz, 1H), 7.34 (d, J=5.5 Hz, 1H),1.41 (s, 12H); ¹³C NMR (125 MHz, CDCl₃) δ 145.8, 139.4, 132.0, 127.5,126.7, 123.7, 123.4, 84.4, 25.1. IR (Neat Film, NaCl) 2977, 1564, 1504,1461, 1372, 1330, 1300, 1267, 1199, 1165, 1135, 1097, 1038, 969, 851,829, 801, 714, 672 cm⁻¹; HRMS (EI+) calc'd for C₁₄H₁₇BSO₂ [M.+]:260.1042, found 260.1039.

Example 8.5: Synthesis of a sila-heterocycle by inter-/intramolecularDouble C—H silylation:9,9-Diethyl-9H-benzo[d]pyrrolo[1,2-a][1,3]azasilole 9

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), 1-phenyl-1H-pyrrole (72.0 mg, 0.5mmol, 1 equiv), Et2SiH2 (97 μL, 0.75 mmol, 1.5 equiv), and 0.5 mL of THFat 35° C. for 72 h and then at 65° C. for 72 h. The desired product 9(48.8 mg, 43% yield) was obtained as colorless needles afterpurification by silica gel flash chromatography (100% hexanes). Rf=0.6(100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.51 (ddd, J=7.1, 1.4, 0.6 Hz,1H), 7.46-7.33 (m, 2H), 7.31 (dt, J=7.9, 0.7 Hz, 1H), 7.09 (td, J=7.2,1.0 Hz, 1H), 6.52 (dd, J=3.3, 1.0 Hz, 1H), 6.41 (dd, J=3.3, 2.6 Hz, 1H),1.05-0.96 (m, 6H), 0.96-0.79 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ 148.0,134.1, 130.8, 129.4, 128.5, 123.9, 117.5, 117.1, 113.3, 111.6, 7.5, 4.4;IR (Neat Film, NaCl) 2958, 2921, 2873, 2849, 1658, 1598, 1462, 1471,1451, 1377, 1332, 1260, 1086, 1017, 799, 755, 717 cm⁻¹; HRMS (FAB+)calc'd for C₁₄H₁₈NSi [M+H]+: 228.1208, found 228.1206. The HSQC spectrumof this reaction product has previously been reported in U.S. Pat. No.9,000,167.

Example 8.6: C—H Silylation of Terthiophene

The reaction was conducted according to the General Procedure. Forcondition A: The reaction was performed with KOt-Bu (11.2 mg, 0.1 mmol,20 mol %), 2,2′:5′,2″-terthiophene (124 mg, 0.5 mmol, 1 equiv), Et₃SiH(243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 25° C. for 40 h.Products 10 (204.7 mg, 86% yield) and SI-10 (23.5 mg, 13% yield) wereobtained after purification by silica gel flash chromatography (100%hexanes). For condition B: The reaction was performed with KOt-Bu (11.2mg, 0.1 mmol, 20 mol %), 2,2′:5′,2″-terthiophene (124 mg, 0.5 mmol, 1equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 45° C.for 65 h. Product 10 (228.6 mg, 96% yield) was obtained afterpurification by silica gel flash chromatography (100% hexanes); SI-10was observed as a trace product by ¹H NMR and GC-MS, but was notisolated.

5,5″-Bis(triethylsilyl)-2,2′:5′,2″-terthiophene 10

Yellow oil, Rf=0.5 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.25 (d,J=3.5 Hz, 2H), 7.14 (d, J=3.5 Hz, 2H), 7.10 (s, 2H), 1.03 (m, 18H), 0.82(m, 12H). ¹³C NMR (125 MHz, CDCl₃) δ 142.4, 136.7, 136.5, 135.7, 124.9,124.5, 7.2, 4.4; IR (Neat Film, NaCl) 3057, 2953, 2934, 2908, 2874,1750, 1455, 1428, 1417, 1377, 1303, 1236, 1212, 1198, 1068, 988, 1009,911, 892, 792, 736, 723 cm⁻¹; HRMS (EI+) calc'd for C₂₄H₃₆S₃Si₂ [M.+]:476.1518, found 476.1534.

[2,2′:5′,2″-Terthiophen]-5-yltriethylsilane SI-10

Yellow oil, Rf=0.4 (100% hexanes); ¹H NMR (500 MHz, CDCl₃) δ 7.24 (d,J=3.4 Hz, 1H), 7.21 (dd, J=5.1, 1.2 Hz, 1H), 7.17 (dd, J=3.6, 1.2 Hz,1H), 7.14 (dd, J=3.4, 1.6 Hz, 1H), 7.09 (q, J=3.7 Hz, 2H), 7.02 (dd,J=5.1, 3.6 Hz, 1H), 1.07-0.98 (m, 9H), 0.82 (qd, J=7.8, 0.9 Hz, 6H); ¹³CNMR (125 MHz, CDCl₃) δ 142.3, 137.5, 136.8, 136.6, 136.4, 135.6, 128.0,125.0, 124.6, 124.5, 124.5, 123.8, 7.5, 4.6; IR (Neat Film, NaCl) 3068,2953, 2873, 1458, 1425, 1377, 1235, 1195, 1069, 1011, 989, 913, 865,836, 793, 737 cm⁻¹; HRMS (FAB+) calc'd for C₁₈H₂₃S₃Si [M+H]+: 363.0731,found 363.0742.

Example 8.7: C—H Silylation of EDOT:(2,3-Dihydrothieno[3,4-b][1,4]dioxin-5-yl)triethylsilane 11

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), EDOT(2,3-dihydrothieno[3,4-b][1,4]dioxine, 71.1 mg, 0.5 mmol), Et₃SiH (240μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 45° C. for 72 h. Thedesired product 11 (79.3 mg, 62% yield) was obtained after purificationby silica gel flash chromatography (gradient elution, 0→5% EtOAc inhexanes) as a cloudy yellow oil. Rf=0.3 (100% hexanes); ¹H NMR (500 MHz,CDCl₃) δ 6.56 (s, 2H), 4.17 (s, 4H), 0.98 (td, J=7.8, 0.8 Hz, 9H),0.84-0.74 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 147.5, 142.5, 108.7,105.0, 64.5, 64.5, 7.4, 3.9; IR (Neat Film NaCl) 2952, 2873, 1468, 1440,1422, 1361, 1244, 1181, 1151, 1072, 1042, 1009, 899, 721 cm⁻¹; HRMS(EI+) calc'd for C₁₂H₂₁O₂SSi [M+H]+: 257.1032, found 257.1064.

Example 8.8: Late Stage Silylation of Active Pharmaceutical Ingredients(APIs) Example 8.8.1:1-Methyl-N-phenyl-N-((5-(triethylsilyl)thiophen-2-yl)methyl)piperidin-4-amine12

The reaction was conducted according to the General Procedure by heatingKOt-Bu (2.2 mg, 0.02 mmol, 20 mol %), thenalidine (28.2 mg, 0.1 mmol, 1equiv), Et₃SiH (48 μL, 0.3 mmol, 3 equiv), and 0.1 mL of THF at 45° C.for 72 h. The desired product 12 (24.9 mg, 62% yield) was obtained as acolorless oil after purification by silica gel flash chromatography(hexanes:EtOAc:Et₃N=100:100:1). Rf=0.2 (hexanes:EtOAc:Et₃N=20:20:1); ¹HNMR (500 MHz, CDCl₃) δ 7.24-7.17 (m, 2H), 7.05 (d, J=3.4 Hz, 1H), 6.97(d, J=3.3 Hz, 1H), 6.82 (dt, J=7.8, 1.0 Hz, 2H), 6.72 (tt, J=7.2, 1.0Hz, 1H), 4.62 (s, 2H), 3.70 (tt, J=11.6, 4.0 Hz, 1H), 2.96-2.92 (m, 2H),2.30 (s, 3H), 2.07 (td, J=11.9, 2.5 Hz, 2H), 1.93-1.85 (m, 2H),1.85-1.73 (m, 2H), 0.97 (t, J=7.9 Hz, 9H), 0.76 (q, J=7.8 Hz, 6H); ¹³CNMR (125 MHz, CDCl₃) δ 151.0, 149.0, 135.2, 134.7, 129.3, 125.3, 117.3,113.8, 55.8, 55.6, 46.4, 46.0, 29.6, 7.5, 4.6. IR (Neat Film, NaCl)2951, 2873, 2780, 2734, 1597, 1574, 1503, 1459, 1377, 1352, 1278, 1237,1207, 1131, 1068, 1008, 987, 850, 802, 745 cm⁻¹; HRMS (MM: ESI-APCI+)calc'd for C₂₃H₃₇N₂SSi [M+H]+: 401.2441, found 401.2460.

Example 8.8.2:5-(2-Chlorobenzyl)-2-(triethylsilyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine13a

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), ticlopidine (132.5 mg, 0.5 mmol, 1equiv), Et₃SiH (243 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 45° C.for 48 h. The desired product 13a (107.7 mg, 57% yield) was obtained asa colorless oil after purification by silica gel flash chromatography(gradient elution, 5→10% Et₂O in hexanes). Rf=0.4 (10% Et₂O in hexanes);¹H NMR (500 MHz, CDCl₃) δ 7.56 (dd, J=7.5, 1.8 Hz, 1H), 7.37 (dd, J=7.8,1.5 Hz, 1H), 7.25 (td, J=7.4, 1.5 Hz, 1H), 7.20 (td, J=7.6, 1.9 Hz, 1H),6.86 (s, 1H), 3.84 (s, 2H), 3.67 (d, J=1.6 Hz, 2H), 2.94 (t, J=5.9 Hz,2H), 2.87 (t, J=5.4 Hz, 2H), 1.02-0.98 (m, 9H), 0.80-0.74 (m, 6H); ¹³CNMR (125 MHz, CDCl₃) δ 139.2, 136.5, 135.6, 134.4, 134.0, 133.2, 130.8,129.6, 128.3, 126.8, 58.7, 53.3, 51.0, 26.1, 7.5, 4.6. IR (Neat Film,NaCl) 2952, 2908, 2873, 2805, 2763, 1462, 1443, 1413, 1375, 1360, 1347,1303, 1289, 1234, 1169, 1125, 1106, 1047, 1032, 1018, 991, 907, 835, 752cm⁻¹; HRMS (MM: ESI-APCI+) calc'd for C₂₀H₂₉ClNSSi [M+H]+: 378.1473,found 378.1480.

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), ticlopidine (134.5 mg, 0.5 mmol, 1equiv), Et₂SiH₂ (194 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 45° C.for 108 h. Products 13b (97.9 mg, 56% yield) and SI-13b (27.3 mg, 18%yield) were obtained after purification by silica gel flashchromatography (gradient elution, 5→50% Et₂O in hexanes).

5-(2-Chlorobenzyl)-2-(diethylsilyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine13b

Colorless oil, Rf=0.4 (10% Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.56 (dd, J=7.6, 1.8 Hz, 1H), 7.38 (dd, J=7.8, 1.4 Hz, 1H), 7.26 (td,J=7.4, 1.5 Hz, 1H), 7.21 (td, J=7.6, 1.9 Hz, 1H), 6.93 (s, 1H), 4.30 (p,J=3.2 Hz, 1H), 3.84 (s, 2H), 3.67 (t, J=1.7 Hz, 2H), 2.96-2.94 (m, 2H),2.88-2.85 (m, 2H), 1.05 (t, J=7.8 Hz, 6H), 0.83 (qd, J=7.5, 3.3 Hz, 4H);¹³C NMR (125 MHz, CDCl₃) δ 140.0, 136.4, 135.9, 134.4, 134.2, 131.3,130.8, 129.6, 128.3, 126.8, 58.6, 53.2, 50.9, 26.1, 8.1, 4.5. IR (NeatFilm, NaCl) 2953, 2909, 2872, 2805, 2112, 1456, 1447, 1361, 1348, 1303,1290, 1231, 1169, 1125, 1106, 1048, 1033, 1009, 992, 907, 810, 752 cm⁻¹;HRMS (MM: ESI-APCI+) calc'd for C₁₈H₂₅ClNSSi [M+H]+: 350.1160, found350.1155.

Bis(5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)diethylsilaneSI-13b

Colorless oil, Rf=0.3 (50% Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃) δ7.55 (dd, J=7.6, 1.8 Hz, 2H), 7.37 (dd, J=7.8, 1.5 Hz, 2H), 7.25 (td,J=7.4, 1.5 Hz, 2H), 7.20 (td, J=7.6, 1.9 Hz, 2H), 6.92 (s, 2H), 3.83 (s,4H), 3.65 (t, J=3.3 Hz, 4H), 2.94 (t, J=5.4 Hz, 4H), 2.86 (t, J=5.6 Hz,4H), 1.09-0.95 (m, 10H); ¹³C NMR (125 MHz, CDCl₃) δ 140.2, 136.4, 135.8,134.53, 134.45, 132.4, 130.9, 129.6, 128.3, 126.8, 58.7, 53.2, 50.9,26.1, 7.5, 6.5. IR (Neat Film, NaCl) 3059, 2953, 2913, 2868, 2806, 1471,1453, 1446, 1361, 1289, 1125, 1105, 1033, 989, 907, 839, 805, 753 cm⁻¹;HRMS (MM: ESI-APCI+) calc'd for C₃₂H₃₇Cl₂N₂S₂Si [M+H]+: 611.1539, found611.1523.

Example 8.8.3:5-(2-Chlorobenzyl)-2-(dimethyl(phenyl)silyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine13c

The reaction was conducted according to the General Procedure by heatingKOt-Bu (11.2 mg, 0.1 mmol, 20 mol %), ticlopidine (134.5 mg, 0.5 mmol, 1equiv), PhMe₂SiH (230 μL, 1.5 mmol, 3 equiv), and 0.5 mL of THF at 45°C. for 108 h. Product 13c (135.4 mg, 68% yield) was obtained as acolorless oil after purification by silica gel flash chromatography (3%Et₂O in hexanes). Rf=0.3 (10% Et₂O in hexanes); ¹H NMR (500 MHz, CDCl₃)δ 7.58-7.52 (m, 3H), 7.39-7.34 (m, 4H), 7.25-7.18 (m, 2H), 6.87 (s, 1H),3.82 (s, 2H), 3.64 (t, J=1.7 Hz, 2H), 2.95-2.92 (m, 2H), 2.88-2.84 (m,2H), 0.56 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 140.1, 138.2, 136.4,135.9, 135.2, 134.4, 134.1, 133.9, 130.8, 129.6, 129.4, 128.3, 128.0,126.8, 58.6, 53.2, 50.9, 26.1, −1.1. IR (Neat Film, NaCl) 3067, 2953,2918, 2806, 2764, 1652, 1471, 1446, 1427, 1361, 1248, 1169, 1109, 1033,990, 907, 832, 810, 777, 753 cm⁻¹; HRMS (MM: ESI-APCI+) calc'd forC₂₂H₂₅ClNSSi [M+H]+: 398.1160, found 398.1152.

Example 8.8.4:5-(Pyridin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine SM-14

To a flame-dried 50 mL Schlenk flask was added4,5,6,7-tetrahydrothieno[3,2-c]pyridine HCl salt (1.0 g, 5.7 mmol),2-(bromomethyl)pyridine HBr salt (2.18 g, 8.6 mmol, 1.5 equiv), Bu₄NHSO4(0.20 g, 0.6 mmol, 10 mol %), K₂CO₃ (3.94 g, 28.5 mmol, 5 equiv), and 10mL of acetonitrile. The flask was purged with argon and the reaction wasstirred at 70° C. for 18 h. The desired product SM-14 (346.5 mg, 26%yield) was obtained after purification by silica gel flashchromatography (gradient elution, 50→100% Et₂O in hexanes) as a yellowoil. Rf=0.1 (50% Et₂O in hexanes). ¹H NMR (500 MHz, CDCl₃) δ 8.58 (ddd,J=4.9, 1.8, 0.9 Hz, 1H), 7.67 (td, J=7.6, 1.8 Hz, 1H), 7.51 (dt, J=7.9,1.0 Hz, 1H), 7.19 (ddd, J=7.5, 4.8, 1.2 Hz, 1H), 7.07 (dt, J=5.1, 0.7Hz, 1H), 6.70 (d, J=5.1 Hz, 1H), 3.89 (s, 2H), 3.64 (t, J=1.7 Hz, 2H),2.96-2.83 (m, 4H); ¹³C NMR (126 MHz, CDCl₃) δ 158.79, 149.20, 136.52,133.78, 133.36, 125.22, 123.13, 122.63, 122.13, 63.82, 53.22, 50.89,25.50; IR (Neat Film, NaCl) 3403, 3062, 2918, 2813, 1648, 1588, 1569,1473, 1431, 1356, 1320, 1236, 1167, 1109, 1053, 1015, 993, 905, 840,809, 761 cm⁻¹; HRMS (EI+) calc'd for C₁₃H₁₃SN₂ [(M+H)−H2]+: 229.0799,found 229.0806.

Example 8.8.5:5-(Pyridin-2-ylmethyl)-2-(triethylsilyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine14

The reaction was conducted according to the General Procedure by heatingKOt-Bu (4.5 mg, 0.04 mmol, 20 mol %),5-(pyridin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine SM-14(46.1 mg, 0.2 mmol), Et₃SiH (96 μL, 0.6 mmol, 3 equiv), and 0.2 mL ofTHF at 45° C. for 72 h. The desired product 14 (49.1 mg, 71% yield) wasobtained after purification by silica gel flash chromatography (gradientelution, 75→100% Et₂O in hexanes) as a colourless oil. Rf=0.5 (75% Et₂Oin hexanes); ¹H NMR (500 MHz, CDCl₃) δ 8.56 (ddd, J=4.9, 1.8, 0.9 Hz,1H), 7.66 (td, J=7.7, 1.8 Hz, 1H), 7.50 (dt, J=7.8, 1.0 Hz, 1H), 7.17(ddd, J=7.5, 4.9, 1.2 Hz, 1H), 6.83 (s, 1H), 3.87 (s, 2H), 3.64 (t,J=1.6 Hz, 2H), 2.94 (tt, J=5.3, 1.5 Hz, 2H), 2.86 (dd, J=5.9, 5.0 Hz,2H), 0.97 (t, J=7.9 Hz, 9H), 0.74 (qd, J=7.7, 0.8 Hz, 6H); ¹³C NMR (126MHz, CDCl₃) δ 158.9, 149.1, 138.9, 136.5, 135.3, 133.8, 133.0, 123.1,122.1, 63.9, 53.2, 50.9, 25.8, 7.4, 4.4; IR (Neat Film, NaCl) 3048,2951, 2873, 2806, 1588, 1569, 1448, 1430, 1361, 1289, 1235, 1169, 1114,1031, 1005, 992, 908, 835, 757, 735, 718 cm⁻¹; HRMS (EI+) calc'd forC₁₉H₂₉N₂SSi [M+H]+: 345.1821, found 345.1835.

Example 9: Selected Examples of Silylation Catalyzed by PotassiumHydroxide (KOH)

Contrary to earlier findings, it has now been discovered that KOH can bean effective catalyst for the direct silylation of heteroaromaticsubstances with hydrosilanes under certain conditions. It now appearsthat by modifying the reaction conditions, this catalyst system can beused with every substrate in which potassium tert-butoxide (or otherstrong bases) was previously shown to be effective, as described in U.S.patent application Ser. No. 14/043,929 and International Application No.PCT/US2013/062963, both filed Oct. 2, 2013 and as described in theinstant specification. However, the use of KOH offers importantpractical benefits such as lower cost and toxicity, and facilitatedreaction set up and purification. Additionally, note that slight changesin conditions can reproducibly alter the degree of substitution (see,e.g., FIG. 7, where a change in operating temperature in furan andbithiophene allowed selective mono- (>10:1 mono-:bis- at 45° C.; 1.2equivalents silane) and bis-silyl-substitution (>10:1 bis-:mono- at 65°C.; 3 equivalents silane).

As shown above in Example 2, Table 1, KOH was found to be completelynon-reactive in this regard under the conditions of the screening tests,and so was believed to be completely inactive in this chemistry. Thefailure of the reaction to proceed under the conditions described inTable 1 has been repeated and confirmed:

However, by adjusting the reaction conditions, the reaction has beenfound to proceed with good conversion. This remarkable change inreactivity with only a slight increase in temperature was completelyunexpected.

See also Table 6 and FIGS. 5A/B and FIG. 6.

TABLE 6 Effect of KOH catalyst loading on the silylation of1-methylindole with 3 equiv. Et₃SiH at 65° C.

KOH, mol % C2-silylation yield 1.6 79 7.9 74 15.9 84 32 78 79 51 159 44318 14

That this catalyst system can operate on the same range of substrates asdescribed for the butoxide/hydride systems is supported by the nowdiscovered operability of the following range of substrates (FIG. 7).

As those skilled in the art will appreciate, numerous modifications andvariations of the present invention are possible in light of theseteachings, and all such are contemplated hereby. For example, inaddition to the embodiments described herein, the present inventioncontemplates and claims those inventions resulting from the combinationof features of the invention cited herein and those of the cited priorart references which complement the features of the present invention.Similarly, it will be appreciated that any described material, feature,or article may be used in combination with any other material, feature,or article, and such combinations are considered within the scope ofthis invention.

Some or all of the following references may be useful in understandingsome elements of the present invention or background principles thereof.

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Each patent, patent application, and publication cited or described inthis document is hereby incorporated herein by reference, each in itsentirety, for all purposes.

What is claimed:
 1. A method of forming an N—Si silyl bond, the methodcomprising contacting an organic substrate comprising an aliphatic aminehaving at least one N—H bond with a mixture comprising of (a) at leastone hydrosilane and (b) at least one hydroxide or alkoxide, underconditions sufficient to form the N—Si bond.
 2. The method of claim 1,wherein the mixture is free of added transition-metal species.
 3. Themethod of claim 1, wherein the at least one hydrosilane comprises ahydrosilane of Formula (I) or Formula (II):(R)_(4-m)Si(H)_(m)  (I)R—[—SiH(R)—O—]_(n)—R  (II) where m is 1, 2, or 3; n is 10 to 100; andeach R is independently optionally substituted C₁₋₁₂ alkyl or C₁₋₁₂heteroalkyl, optionally substituted C₆₋₂₀ aryl or C₅₋₂₀ heteroaryl,optionally substituted C₇₋₃₀ alkaryl or C₆₋₃₀ heteroalkaryl, optionallysubstituted C₇₋₃₀ aralkyl or C₆₋₃₀ heteroaralkyl, optionally substituted—O—C₁₋₁₂ alkyl or —O—C₁₋₁₂ heteroalkyl, optionally substituted —O—C₇₋₂₀aryl or —O—C₅₋₂₀ heteroaryl, optionally substituted —O—C₇₋₃₀ alkaryl or—O—C₆₋₃₀ heteroalkaryl, or optionally substituted —O—C₇₋₃₀ aralkyl or—O—C₆₋₃₀ heteroaralkyl, and, if substituted, the substituents may bephosphonato, phosphoryl, phosphanyl, phosphino, sulfonato, C₁-C₂₀alkylsulfanyl, C₆₋₂₀ arylsulfanyl, C₁-C₂₀ alkylsulfonyl, C₆₋₂₀arylsulfonyl, C₁-C₂₀ alkylsulfinyl, C₆₋₂₀ arylsulfinyl, sulfonamido,amino, amido, imino, nitro, nitroso, hydroxyl, C₁-C₂₀ alkoxy, C₆₋₂₀aryloxy, C₂-C₂₀ alkoxycarbonyl, C₅-C₂₀ aryloxycarbonyl, carboxyl,carboxylato, mercapto, formyl, C₁-C₂₀ thioester, cyano, cyanato,thiocyanato, isocyanate, thioisocyanate, carbamoyl, epoxy, styrenyl,silyl, silyloxy, silanyl, siloxazanyl, boronato, boryl, or halogen, or ametal-containing or metalloid-containing group, where the metalloid isSn or Ge, or where the substituents optionally provide a tether to aninsoluble or sparingly soluble support media comprising alumina, silica,or carbon.
 4. The method of claim 3, wherein the at least onehydrosilane comprises a hydrosilane of Formula (I).
 5. The method ofclaim 3, wherein m is 1 or
 2. 6. The method of claim 3, where each R isindependently C₁-C₆ alkyl, phenyl, tolyl, benzyl, phenethyl, orpyridinyl.
 7. The method of claim 3, where each R is independently C₁-C₆alkyl.
 8. The method of claim 3, wherein the at least one hydrosilanecomprises (R)₃SiH, where each R is independently methyl, ethyl, propyl,or butyl.
 9. The method of claim 1, wherein the at least one hydrosilanecomprises a polymethylhydrosiloxane.
 10. The method of claim 1, whereinthe aliphatic amine having at least one N—H bond is a secondary amine.11. The method of claim 10, wherein the aliphatic amine having at leastone N—H bond is a primary or secondary amine.
 12. The method of claim 1,wherein the hydroxide is potassium hydroxide (KOH).
 13. The method ofclaim 1, wherein the alkoxide is a potassium alkoxide.
 14. The method ofclaim 13, wherein the alkoxide is a potassium tert-butoxide.